Substituted carbonucleoside derivatives useful as anticancer agents

ABSTRACT

Compounds of the general formula): 
     
       
         
         
             
             
         
       
     
     processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.

FIELD OF THE INVENTION

This invention relates to novel carbonucleoside derivatives useful inthe treatment of abnormal cell growth, such cancer, in mammals. Thisinvention also relates to a method of using such compounds in thetreatment of abnormal cell growth in mammals, especially humans, and topharmaceutical compositions as anticancer agents.

BACKGROUND OF THE INVENTION

Post-translational modification of arginine residues by methylation isimportant for many critical cellular processes including chromatinremodeling, gene transcription, protein translation, signaltransduction, RNA splicing and cell proliferation. Arginine methylationis catalyzed by protein arginine methyltransferase (PRMT) enzymes. Thereare nine PRMT members in all, and eight have reported enzymatic activityon target substrates.

The protein arginine methyltransferase (PRMT) family of enzymes utilizeS-adenosyl methionine (SAM) to transfer methyl groups to arginineresidues on target proteins. Type I PRMTs catalyze formation ofmono-methyl arginine and asymmetric di-methyl arginines while Type IIPRMTs catalyze mono-methyl arginine and symmetric di-methyl arginines.PRMT5 is a Type II enzyme, twice transferring a methyl group from SAM tothe two ω-guanidino nitrogen atoms of arginine, leading to ω-NG, N′Gdi-symmetric methylation of protein substrates.

PRMT5 protein is found in both the nucleus and cytoplasm, and hasmultiple protein substrates such as histones, transcription factors andspliceosome proteins. PRMT5 has a binding partner, Mep50 (methylosomeprotein 50) and functions in multiple protein complexes. PRMT5 isassociated with chromatin remodeling complexes (SWI/SNF, NuRD) andepigenetically controls genes involved in development, cellproliferation, and differentiation, including tumor suppressors, throughmethylation of histones (Karkhanis, V. et al., Versatility of PRMT5Induced Methylation in Growth Control and Development, Trends BiochemSci 36(12) 633-641 (2011)). PRMT5 also controls gene expression throughassociation with protein complexes that recruit PRMT5 to methylateseveral transcription factors p53 (Jansson, M. et al., ArginineMethylation Regulates the p53 Response, Nat. Cell Biol. 10, 1431-1439(2008)); E2F1 (Zheng, S. et al., Arginine Methylation-DependentReader-Writer Interplay Governs Growth Control by E2F-1, Mol Cell 52(1),37-51 (2013)); HOXA9 (Bandyopadhyay, S. et al., HOXA9 Methylation byPRMT5 is Essential for Endothelial Cell Expression of Leukocyte AdhesionMolecules, Mol. Cell. Biol. 32(7):1202-1213 (2012)); and NFκB (Wei, H.et al., PRMT5 dimethylates R30 of the p65 Subunit to Activate NFκB, PNAS110(33), 13516-13521 (2013)). In the cytoplasm, PRMT5 has a diverse setof substrates involved in other cellular functions including RNAsplicing (Sm proteins), golgi assembly (gm130), ribosome biogenesis(RPS10), piRNA mediated gene silencing (Piwi proteins) and EGFRsignaling (Karkhanis, 2011).

Additional papers relating to PRMT5 include: Aggarwal, P. et al., (2010)Nuclear Cyclin D1/CDK4 Kinase Regulates CUL4B Expression and TriggersNeoplastic Growth via Activation of the PRMT5 Methyltransferase, CancerCell 18: 329-340; Bao, X. et al., Overexpression of PRMT5 Promotes TumorCell Growth and is Associated with Poor Disease Prognosis in EpithelialOvarian Cancer, J Histochem Cytochem 61: 206-217 (2013); Cho E. et al.,Arginine Methylation Controls Growth Regulation by E2F1, EMBO J. 31(7)1785-1797 (2012); Gu, Z. et al., Protein Arginine Methyltransferase 5Functions in Opposite Ways in the Cytoplasm and Nucleus of ProstateCancer Cells, PLoS One 7(8) e44033 (2012); Gu, Z. et al., ProteinArginine Methyltransferase 5 is Essential for Growth of Lung CancerCells, Biochem J. 446: 235-241 (2012); Kim, J. et al., Identification ofGastric Cancer Related Genes Using a cDNA Microarray Containing NovelExpressed Sequence Tags Expressed in Gastric Cancer Cells, Clin CancerRes. 11(2) 473-482 (2005); Nicholas, C. et al., PRMT5 is Upregulated inMalignant and Metastatic Melanoma and Regulates Expression of MITF andp27(Kip1), PLoS One 8(9) e74710 (2012); Powers, M. et al., ProteinArginine Methyltransferase 5 Accelerates Tumor Growth by ArginineMethylation of the Tumor Suppressor Programmed Cell Death 4, Cancer Res.71(16) 5579-5587 (2011); Wang, L. et al., Protein ArginineMethyltransferase 5 Suppresses the Transcription of the RB Family ofTumor Suppressors in Leukemia and Lymphoma Cells, Mol. Cell Biol.28(20), 6262-6277 (2008).

PRMT5 is overexpressed in many cancers and has been observed in patientsamples and cell lines including B-cell lymphoma and leukemia (Wang,2008) and the following solid tumors: gastric (Kim 2005) esophageal(Aggarwal, 2010), breast (Powers, 2011), lung (Gu, 2012), prostate (Gu,2012), melanoma (Nicholas 2012), colon (Cho, 2012) and ovarian (Bao,2013). In many of these cancers, overexpression of PRMT5 correlated withpoor prognosis. Aberrant arginine methylation of PRMT5 substrates hasbeen linked to other indications in addition to cancer, such asmetabolic disorders, inflammatory and autoimmune disease andhemaglobinopathies.

SUMMARY OF THE INVENTION

Given its role in regulating various biological processes, PRMT5 is anattractive target for modulation with small molecule inhibitors. Todate, few effective PRMT5 inhibitors have been developed, and no PRMT5inhibitors have entered the clinic.

Each of the embodiments of the compounds of the present inventiondescribed below can be combined with any other embodiment of thecompounds of the present invention described herein not inconsistentwith the embodiment with which it is combined. Furthermore, each of theembodiments below describing the invention envisions within its scopepharmaceutically acceptable salts of the compounds of the invention.Accordingly, the phrase “or a pharmaceutically acceptable salt thereof”is implicit in the description of all compounds described herein.

The invention includes embodiments wherein there is provided a compoundof formula (I):

Embodiments of the present invention include compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:R¹ is selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl, 5-12 memberedheteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ andN(R⁴)₂, where each R⁴ is independently A-R¹⁴, where A is absent,(C₁-C₃)alkyl, —C(O)— or —SO₂—, and R¹⁴ is hydrogen, (C₁-C₈)alkyl,(C₅-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl or 3-12membered heterocyclyl, or two R⁴ join to form a 4-6 memberedheterocyclic ring containing 1-3 heteroatoms selected from N, O and S;R² is hydrogen, halogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy or N(R⁵)₂,where each R⁵ is independently hydrogen or (C₁-C₈)alkyl, or two R⁵ jointo form a 4-6 membered heterocyclic ring containing 1-3 heteroatomsselected from N, O and S;

each R³ is independently selected from hydrogen, hydroxy, NH₂;(C₁-C₈)alkyl or heteroalkyl having 1-8 atoms, or when D is C(R³)₂, R³ isadditionally selected from fluorine, (C₁-C₈)alkylene or heteroalkylenebound to an atom on G to form a ring fused to G, where R³ is optionallysubstituted with 1-6 R⁸;

each R⁹ is independently hydrogen or fluorine;D is C(R³)₂, NR³, O, S or S(O)₁₋₂;G is a (C₅-C₁₂)aryl or a 5-12 membered heteroaryl ring system fused to(C₃-C₁₀)cycloalkyl or heterocyclyl ring system;each R⁸ is absent or is independently selected from the group consistingof (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl,5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 memberedheterocyclyl, OR⁴, SR⁴, N(R⁴)₂, CN, halogen and CON(R⁴)₂, where two R⁸optionally join to form a 4-6 membered spiro-cycloalkyl ring, acycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸optionally join to form carbonyl;where each R⁴ is independently A-R¹⁴, where A is absent, (C₁-C₃)alkyl,—C(O)— or —SO₂—, and R¹⁴ is hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl, 5-12membered heteroaryl, (C₃-C₁₀)cycloalkyl or 3-12 membered heterocyclyl,or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3heteroatoms selected from N, O and S;Q is absent or is a divalent moiety selected from O, S, NH and(C₁-C₈)alkylene;V is N or C if Z is present, where if V forms a double bond V is carbon,or V is N or CH and forms a double bond with W if Z is absent;W is N or C, where if W forms a double bond if W is carbon;X is N or C if Y is present, where if X forms a double bond X is carbon,or X is O, NR¹⁶ or C(R¹⁶)₂ if Y is absent, where R¹⁶ is H or methyl;Y is absent, CR¹⁰, N, NR¹⁰, O or S, or Y is absent, hydrogen or(C₁-C₈)alkyl if Z is absent, where each R¹⁰ is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, halogen, SH,S—(C₁-C₈)alkyl and N(R¹¹)₂ if Y is CR¹⁰, where Y forms a double bondwith an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ isindependently hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 memberedheteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ringcontaining 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)₂ andthe two R¹⁰ and the carbon to which they are associated form a carbonylor a thiocarbonyl;Z is absent, CR¹², N, NR¹², O or S, or Z is absent, hydrogen or(C₁-C₈)alkyl if Y is absent, where each R¹² is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, fluoro, chloro,bromo, SH, S—(C₁-C₈)alkyl and N(R¹³)₂, where Z forms a double bond withan adjacent ring member if it is CR¹² or N, where each R¹³ isindependently hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 memberedheteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ringcontaining 1-3 heteroatoms selected from N, O and S, and where Z is notNR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and thetwo R¹² and the carbon to which they are associated form a carbonyl or athiocarbonyl; andeach ----- is absent or an optional bond, where no more than two,non-adjacent ----- may be present.

Embodiments of the present invention also include compounds of formula(II):

or a pharmaceutically acceptable salt thereof, wherein:R¹ is selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl, 5-12 memberedheteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ andN(R⁴)₂, where each R⁴ is independently A-R¹⁴, where A is absent,(C₁-C₃)alkyl, —C(O)— or —SO₂—, and R¹⁴ is hydrogen, (C₁-C₈)alkyl,(C₅-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl or 3-12membered heterocyclyl, or two R⁴ join to form a 4-6 memberedheterocyclic ring containing 1-3 heteroatoms selected from N, O and S;R² is hydrogen, halogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy or N(R⁵)₂,where each R⁵ is independently hydrogen or (C₁-C₈)alkyl, or two R⁵ jointo form a 4-6 membered heterocyclic ring containing 1-3 heteroatomsselected from N, O and S;

each R³ is independently selected from hydrogen, hydroxy, NH₂;(C₁-C₈)alkyl or heteroalkyl having 1-8 atoms, or when D is C(R³)₂, R³ isadditionally selected from fluorine, (C₁-C₈)alkylene or heteroalkylenebound to an atom on G to form a ring fused to G, where R³ is optionallysubstituted with 1-6 R⁸;

each R⁹ is independently hydrogen or fluorine;D is C(R³)₂, O, or S(O)₁₋₂;G is a (C₅-C₁₂)aryl, 5-12 membered heteroaryl ring system;R¹⁵ is heteroalkyl having 1-8 atoms bound to an atom on G and optionallysubstituted with 1-6 R⁸, or R¹⁵ is heteroalkylene bound to an atom on G,optionally substituted with 1-6 R⁸, and bound to an adjacent atom on G(i.e., the two ends of R¹⁵ when R¹⁵ is heteroalkylene are bound toadjacent carbons on the G ring);each R⁸ is absent or is independently selected from the group consistingof (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl,5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 memberedheterocyclyl, OR⁴, SR⁴, N(R⁴)₂, CN, halogen and CON(R⁴)₂, where two R⁸optionally join to form a 4-6 membered spiro-cycloalkyl ring, acycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸optionally join to form carbonyl;where each R⁴ is independently A-R¹⁴, where A is absent, (C₁-C₃)alkyl,—C(O)— or —SO₂—, and R¹⁴ is hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl, 5-12membered heteroaryl, (C₃-C₁₀)cycloalkyl or 3-12 membered heterocyclyl,or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3heteroatoms selected from N, O and S;Q is absent or is a divalent moiety selected from O, S, NH and(C₁-C₈)alkylene;V is N or C, where if V forms a double bond V is carbon;W is N or C, where if W forms a double bond W is carbon;X is N or C, where if X forms a double bond X is carbon;Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, or R¹⁰ isoptionally selected from halogen, SH, S—(C₁-C₈)alkyl and N(R¹¹)₂ if Y isCR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰or N, and where each R¹¹ is independently hydrogen, (C₁-C₈)alkyl,(C₅-C₁₂)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6membered heterocyclic ring containing 1-3 heteroatoms selected from N, Oand S, or Y is C(R¹⁰)₂ and the two R¹⁰ and the carbon to which they areassociated form a carbonyl or a thiocarbonyl;Z is CR¹², N, NR¹², O or S, where each R¹² is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, or R¹² isoptionally selected from fluoro, chloro, bromo, iodo, SH, S—(C₁-C₈)alkyland N(R¹³)₂ if Z is CR¹², where Z forms a double bond with an adjacentring member if it is CR¹² or N, where each R¹³ is independentlyhydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 membered heteroaryl, or twoR¹³ join to form a 4-6 membered heterocyclic ring containing 1-3heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N,V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and the two R¹² and thecarbon to which they are associated form a carbonyl or a thiocarbonyl;andeach ----- is an optional bond, where no more than two, non-adjacent----- may be present, provided that D is S(O)₁₋₂ when G is C₁₀ aryl or a10-membered heteroaryl.

Additional embodiments of the present invention include compounds offormula (III):

or a pharmaceutically acceptable salt thereof, wherein:each R¹ is independently selected from the group consisting of(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl,5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 memberedheterocyclyl, OR⁴, SR⁴ and N(R⁴)₂, where each R⁴ is independently A-R¹⁴,where A is absent, (C₁-C₃)alkyl, —C(O)— or —SO₂—, and R¹⁴ is hydrogen,(C₁-C₈)alkyl, (C₅-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-C₁₀)cycloalkylor 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 memberedheterocyclic ring containing 1-3 heteroatoms selected from N, O and S;R² is hydrogen, halogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy or N(R⁵)₂,where each R⁵ is independently hydrogen or (C₁-C₈)alkyl, or two R⁵ jointo form a 4-6 membered heterocyclic ring containing 1-3 heteroatomsselected from N, O and S;each R³ is independently hydrogen, hydroxy or NH₂; or when D is C(R³)₂,R³ is additionally selected from fluorine;each R⁹ is independently hydrogen or fluorine;D is C(R³)₂, O, or S(O)₁₋₂;E is NR¹, CH₂, C(R¹)₂, O or —S(O)₂;each R⁸ is absent or is independently selected from the group consistingof (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl,5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 memberedheterocyclyl, OR⁴, SR⁴, N(R⁴)₂, CN, halogen and CON(R⁴)₂, where two R⁸optionally join to form a 4-6 membered spiro-cycloalkyl ring, acycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸optionally join to form carbonyl;where each R⁴ is independently A-R¹⁴, where A is absent, (C₁-C₃)alkyl,—C(O)— or —SO₂—, and R¹⁴ is hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl, 5-12membered heteroaryl, (C₃-C₁₀)cycloalkyl or 3-12 membered heterocyclyl,or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3heteroatoms selected from N, O and S;Q is absent or is a divalent moiety selected from O, S, NH and(C₁-C₈)alkylene;V is N or C, where if V forms a double bond V is carbon;W is N or C, where if W forms a double bond W is carbon;X is N or C, where if X forms a double bond X is carbon;Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, halogen, SH,S—(C₁-C₈)alkyl and N(R¹¹)₂ if Y is CR¹⁰, where Y forms a double with anadjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ isindependently hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 memberedheteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ringcontaining 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)₂ andthe two R¹⁰ and the carbon to which they are associated form a carbonylor a thiocarbonyl;Z is CR¹², N, NR¹², O or S, where each R¹² is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, fluoro, chloro,bromo, SH, S—(C₁-C₈)alkyl and N(R¹³)₂, where Z forms a double bond withan adjacent ring member if it is CR¹² or N, where each R¹³ isindependently hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 memberedheteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ringcontaining 1-3 heteroatoms selected from N, O and S, and where Z is notNR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and thetwo R¹² and the carbon to which they are associated form a carbonyl or athiocarbonyl; and each ----- is an optional bond, where no more thantwo, non-adjacent ----- may be present.

Additional embodiments of the present invention include compounds offormula (IV):

or a pharmaceutically acceptable salt thereof, wherein:each R¹ is independently selected from the group consisting of(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl,5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 memberedheterocyclyl, OR⁴, SR⁴ and N(R⁴)₂, where each R⁴ is independently A-R¹⁴,where A is absent, (C₁-C₃)alkyl, —C(O)— or —SO₂—, and R¹⁴ is hydrogen,(C₁-C₈)alkyl, (C₅-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-C₁₀)cycloalkylor 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 memberedheterocyclic ring containing 1-3 heteroatoms selected from N, O and S;R² is hydrogen, halogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy or N(R⁵)₂,where each R⁵ is independently hydrogen or (C₁-C₈)alkyl, or two R⁵ jointo form a 4-6 membered heterocyclic ring containing 1-3 heteroatomsselected from N, O and S;each R³ is independently hydrogen, hydroxy or NH₂; or when D is C(R³)₂,R³ is additionally selected from fluorine;each R⁹ is independently hydrogen or fluorine;

B is N or C;

E is NR¹, CH₂, C(R¹)₂, O or —S(O)₂;each R⁸ is absent or is independently selected from the group consistingof (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, hydroxy, (C₁-C₈)alkoxy, (C₅-C₁₂)aryl,5-12 membered heteroaryl, (C₃-C₁₀)cycloalkyl, 3-12 memberedheterocyclyl, OR⁴, SR⁴, N(R⁴)₂, CN, halogen and CON(R⁴)₂, where two R⁸optionally join to form a 4-6 membered spiro-cycloalkyl ring, acycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸optionally join to form carbonyl;where each R⁴ is independently A-R¹⁴, where A is absent, (C₁-C₃)alkyl,—C(O)— or —SO₂—, and R¹⁴ is hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl, 5-12membered heteroaryl, (C₃-C₁₀)cycloalkyl or 3-12 membered heterocyclyl,or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3heteroatoms selected from N, O and S;Q is absent or is a divalent moiety selected from O, S, NH and(C₁-C₈)alkylene;V is N or C, where if V forms a double bond V is carbon;W is N or C, where if W forms a double bond W is carbon;X is N or C, where if X forms a double bond X is carbon;Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, halogen, SH,S—(C₁-C₈)alkyl and N(R¹¹)₂ if Y is CR¹⁰, where Y forms a double with anadjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ isindependently hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 memberedheteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ringcontaining 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)₂ andthe two R¹⁰ and the carbon to which they are associated form a carbonylor a thiocarbonyl;Z is CR¹², N, NR¹², O or S, where each R¹² is independently selectedfrom hydrogen, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy, fluoro, chloro,bromo, SH, S—(C₁-C₈)alkyl and N(R¹³)₂, where Z forms a double bond withan adjacent ring member if it is CR¹² or N, where each R¹³ isindependently hydrogen, (C₁-C₈)alkyl, (C₅-C₁₂)aryl or 5-12 memberedheteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ringcontaining 1-3 heteroatoms selected from N, O and S, and where Z is notNR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and thetwo R¹² and the carbon to which they are associated form a carbonyl or athiocarbonyl; and each ----- is an optional bond, where no more thantwo, non-adjacent ----- may be present.Further embodiments of the present invention include compounds asdescribed herein where

is selected from:

In certain embodiments:

is selected from:

Further embodiments of the present invention include compounds asdescribed herein where

is selected from:

In certain embodiments

isis:

Further embodiments of the present invention include compounds selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of the present invention the compound is selectedfrom:

or a pharmaceutically acceptable salt thereof.

Further embodiments of the present invention include compounds selectedfrom:

or a pharmaceutically acceptable salt thereof.

Also provided in the present invention are pharmaceutical compositionscomprising a compound as described herein and a pharmaceuticallyacceptable carrier.

Additionally, provided in the present invention are methods of treatingabnormal cell growth in a mammal comprising administering to the mammala therapeutically effective amount of a compound as described herein.The abnormal cell growth is cancer. The cancer referred to herein may belung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of thehead or neck, cutaneous or intraocular melanoma, uterine cancer, ovariancancer, rectal cancer, cancer of the anal region, stomach cancer, coloncancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, or pituitary adenoma.

Further still, the present invention provides for the use of a compoundas described herein for the preparation of a medicament useful in thetreatment of abnormal cell growth in a mammal. The abnormal cell growthis cancer. The cancer referred to herein may be lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, or pituitary adenoma.

The invention further provides for embodiments wherein:

As found in formula I or formula II is selected from:

Additional embodiments of the invention include pharmaceuticalcomposition comprising of a compound described herein or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Additional embodiments of the invention include methods of treatingabnormal cell growth in a mammal, the method comprising administering tothe mammal a therapeutically effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

Additional embodiments of the invention include such methods oftreatment as are described herein, wherein the abnormal cell growth iscancer. In particular, such methods wherein the cancer is lung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, or pituitary adenoma.

There is also provided an embodiment of the invention which is the useof a compound described herein, or a pharmaceutically acceptable saltthereof for the preparation of a medicament useful in the treatment ofabnormal cell growth in a mammal, particularly wherein the abnormal cellgrowth is cancer, and more particularly wherein the cancer is lungcancer, bone cancer, pancreatic cancer, skin cancer, cancer of the heador neck, cutaneous or intraocular melanoma, uterine cancer, ovariancancer, rectal cancer, cancer of the anal region, stomach cancer, coloncancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, or pituitary adenoma.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of the invention or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a method of treatingabnormal cell growth in a mammal, including a human, the methodcomprising administering to the mammal a therapeutically effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt thereof. In another embodiment, the abnormal cell growth is cancer.In another embodiment, the cancer is lung cancer, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, or pituitary adenoma.

Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings discussed below. Variables defined in thissection, such as R, X, n and the like, are for reference within thissection only, and are not meant to have the same meaning as may be usedoutside of this definitions section. Further, many of the groups definedherein can be optionally substituted. The listing in this definitionssection of typical substituents is exemplary and is not intended tolimit the substituents defined elsewhere within this specification andclaims.“Alkenyl” refers to an alkyl group, as defined herein, consisting of atleast two carbon atoms and at least one carbon-carbon double bond.Representative examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. “Alkenylene”refers to a di-valent form of alkenyl.“Alkoxy” refers to —O-alkyl where alkyl is preferably C₁-C₈, C₁-C₇,C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂ or C, alkyl.“Alkyl” refers to a saturated aliphatic hydrocarbon radical includingstraight chain and branched chain groups of 1 to 20 carbon atoms(“(C₁-C₂₀)alkyl”), preferably 1 to 12 carbon atoms (“(C₁-C₁₂)alkyl”),more preferably 1 to 8 carbon atoms (“(C₁-C₈)alkyl”), or 1 to 6 carbonatoms (“(C₁-C₆)alkyl”), or 1 to 4 carbon atoms (“(C₁-C₄)alkyl”).Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl,n-butyl, iso-butyl, tert-butyl, pentyl, neopentyl, and the like. Alkylmay be substituted or unsubstituted. Typical substituent groups includecycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl,O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and —NR^(x)R^(y),where R^(x) and R^(y) are for example hydrogen, alkyl, cycloalkyl, aryl,carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, afive- or six-member heteroalicyclic ring. “Haloalkyl” for instance(C₁-C₈)haloalkyl, refers to an alkyl having one or more, halogensubstituents. “Alkylene” refers to a di-valent form of alkyl.“Alkynyl” refers to an alkyl group, as defined herein, consisting of atleast two carbon atoms and at least one carbon-carbon triple bond.Representative examples include, but are not limited to, ethynyl,1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. “Alkynylene”refers to a di-valent form of alkynyl.“Amino” refers to an —NR^(x)R^(Y) group, wherein R^(x) and R^(y) areboth hydrogen.“(C₆-C₁₂)aryl” refers to an all-carbon monocyclic or fused-ringpolycyclic groups of 6 to 12 carbon atoms having a completely conjugatedpi-electron system. Similarly, “(C₅-C₁₂)aryl” refers to an all-carbonmonocyclic or fused-ring polycyclic groups of 5 to 12 carbon atomshaving a completely conjugated pi-electron system. Examples, withoutlimitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. Thearyl group may be substituted or unsubstituted. Typical substituentsinclude halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy,O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, sulfinyl, sulfonyl, amino and —NR^(x)R^(Y), with R^(x)and R^(y) as defined above.“Cyano” refers to a —C—N group. Cyano may be expressed as CN.“(C₃-C₁₀)cycloalkyl” refers to a 3 to 10 member all-carbon monocyclicring, a 3 to 10 member all-carbon bicyclic ring, an all-carbon5-member/6-member or 6-member/6-member fused bicyclic ring, amulticyclic fused ring (a “fused” ring system means that each ring inthe system shares an adjacent pair of carbon atoms with each other ringin the system) group wherein one or more of the rings may contain one ormore double bonds but none of the rings has a completely conjugatedpi-electron system, and a bridged all-carbon ring system. Examples,without limitation, of cycloalkyl groups are cyclopropane, cyclobutane,cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane,cycloheptane, cycloheptatriene, and the like. A cycloalkyl group may besubstituted or unsubstituted. Typical substituent groups include alkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy,O-carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino and—NR^(x)R^(Y), with R^(x) and R^(y) as defined above.“Halogen” or the prefix “halo” refers to fluoro, chloro, bromo and iodo.Preferably halogen refers to fluoro or chloro.“Heteroalkyl” refers to a straight chain or branched chain alkyl groupof 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, morepreferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbonatoms, wherein one, two or three of which carbon atoms are replaced by aheteroatom selected from from NR^(x), N, O, and S(O)_(n) (where n is 0,1 or 2). Typically the heteroatoms, of there are more that oneheteroatoms, are not adjacent to one another. Exemplary heteroalkylsinclude alkyl ethers, secondary and tertiary alkyl amines, amides, alkylsulfides, and the like. The group may be a terminal group or a bridginggroup. As used herein, reference to the normal chain when used in thecontext of a bridging group refers to the direct chain of atoms linkingthe two terminal positions of the bridging group. As with “alkyl”,typical substituent groups on “heteroalkyl” include cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, 0-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy,O-carboxy, nitro, silyl, amino and —NR^(x)R^(Y), where R^(x) and R^(y)are for example hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl,sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-memberheteroalicyclic ring. “Heteroalkenyl” refers to a heteroalkyl possessingone or more carbon-carbon double bonds. “Heteroalkylene” refers to adi-valent form of heteroalkyl.“Heteroalkenylene” refers to a di-valent form of heteroalkenyl.“Heteroaryl” refers to a monocyclic or fused ring group of 5 to 12carbon ring atoms containing one, two, three or four ring heteroatomsselected from from NR^(x), N, O, and S(O)_(n) (where n is 0, 1 or 2)and, in addition, having a completely conjugated pi-electron system.Preferred heteroaryl groups include (C₂-C₇)heteroaryl in accordance withthe definition above. Examples, without limitation, of unsubstitutedheteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline,purine, tetrazole, triazine, and carbazole. The heteroaryl group may besubstituted or unsubstituted. Typical substituents include alkyl,cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido,C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and —NR^(x)R^(Y)with R^(x) and R^(y) as defined above. A pharmaceutically acceptableheteroaryl is one that is sufficiently stable to be attached to acompound of the invention, formulated into a pharmaceutical compositionand subsequently administered to a patient in need thereof. Examples oftypical monocyclic heteroaryl groups include, but are not limited to:

Examples of suitable fused ring heteroaryl groups include, but are notlimited to:

“Heterocyclyl” refers to a monocyclic or fused ring system having 3 to12 ring atoms containing one, two, three or four ring heteroatomsselected from N, O, and S(O)_(n) (where n is 0, 1 or 2), and 1-9 carbonatoms The rings may also have one or more double bonds. However, therings do not have a completely conjugated pi-electron system. Preferredheterocycles include (C₂-C₆)heterocycles in accordance with thedefinition above. Examples of suitable saturated heteroalicyclic groupsinclude, but are not limited to:

Examples of suitable partially unsaturated heteroalicyclic groupsinclude, but are not limited to:

The heterocyclyl group is optionally substituted with one or twosubstituents independently selected from halo, lower alkyl, lower alkylsubstituted with carboxy, ester hydroxy, or mono or dialkylamino.Moreover, the heterocycle may contain bridging, including bridgingbetween non-adjacent carbons on the heterocycle, with the bridgecontaining 1-2 carbons and 0-1 heteroatoms selected from selected fromNR^(x), O, and S(O)_(n) (where n is 0, 1 or 2).“Hydroxy” or “hydroxyl” refers to an —OH group.“In vitro” refers to procedures performed in an artificial environmentsuch as, e.g., without limitation, in a test tube or culture medium.“In vivo” refers to procedures performed within a living organism suchas, without limitation, a mouse, rat or rabbit.“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocycle group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocycle group is substituted with an alkyl group and situationswhere the heterocycle group is not substituted with the alkyl group.“Organism” refers to any living entity comprised of at least one cell. Aliving organism can be as simple as, for example, a single eukarioticcell or as complex as a mammal, including a human being.A “pharmaceutically acceptable excipient” refers to an inert substanceadded to a pharmaceutical composition to further facilitateadministration of a compound. Examples, without limitation, ofexcipients include calcium carbonate, calcium phosphate, various sugarsand types of starch, cellulose derivatives, gelatin, vegetable oils andpolyethylene glycols.As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which retain the biological effectiveness and properties ofthe parent compound. Such salts include:(i) acid addition salts, which can be obtained by reaction of the freebase of the parent compound with inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, andperchloric acid and the like, or with organic acids such as acetic acid,oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaricacid, citric acid, succinic acid or malonic acid and the like; or(ii) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein, or physiologically/pharmaceuticallyacceptable salts, solvates, hydrates or prodrugs thereof, with otherchemical components, such as physiologically/pharmaceutically acceptablecarriers and excipients. The purpose of a pharmaceutical composition isto facilitate administration of a compound to an organism.As used herein, a “physiologically/pharmaceutically acceptable carrier”refers to a carrier or diluent that does not cause significantirritation to an organism and does not abrogate the biological activityand properties of the administered compound.“Therapeutically effective amount” refers to that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated. In reference to the treatment ofcancer, a therapeutically effective amount refers to that amount whichhas at least one of the following effects:reducing the size of the tumor;inhibiting (that is, slowing to some extent, preferably stopping) tumormetastasis;inhibiting to some extent (that is, slowing to some extent, preferablystopping) tumor growth, and relieving to some extent (or, preferably,eliminating) one or more symptoms associated with the cancer.“Treat”, “treating” and “treatment” refer to a method of alleviating orabrogating a methyltransferase mediated cellular disorder and/or itsattendant symptoms. With regard particularly to cancer, these termssimply mean that the life expectancy of an individual affected with acancer will be increased or that one or more of the symptoms of thedisease will be reduced.

DETAILED DESCRIPTION

General schemes for synthesizing the compounds of the invention can befound in the Examples section herein.

Unless indicated otherwise, all references herein to the inventivecompounds include references to salts, solvates, hydrates and complexesthereof, and to solvates, hydrates and complexes of salts thereof,including polymorphs, stereoisomers, and isotopically labeled versionsthereof.

Pharmaceutically acceptable salts include acid addition and base salts(including disalts). Suitable acid addition salts are formed from acidswhich form non-toxic salts. Examples include the acetate, aspartate,benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate,camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminum, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts. For a review on suitablesalts, see “Handbook of Pharmaceutical Salts: Properties, Selection, andUse” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), thedisclosure of which is incorporated herein by reference in its entirety.

Tosylate, hydrochloride and mesylate salts are of interest.

A pharmaceutically acceptable salt of the inventive compounds can bereadily prepared by mixing together solutions of the compound and thedesired acid or base, as appropriate. The salt may precipitate fromsolution and be collected by filtration or may be recovered byevaporation of the solvent. The degree of ionization in the salt mayvary from completely ionized to almost non-ionized.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when the solvent is water. Pharmaceuticallyacceptable solvates in accordance with the invention include hydratesand solvates wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.Also included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975), the disclosure of which is incorporated herein by reference inits entirety.Also within the scope of the invention are polymorphs, prodrugs, andisomers (including optical, geometric and tautomeric isomers) of theinventive compoundsDerivatives of compounds of the invention which may have little or nopharmacological activity themselves but can, when administered to apatient, be converted into the inventive compounds, for example, byhydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further information on the use of prodrugs may be found in ‘Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and WStella) and ‘Bioreversible Carriers in Drug Design’, Pergamon Press,1987 (ed. E B Roche, American Pharmaceutical Association), thedisclosures of which are incorporated herein by reference in theirentireties.Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the inventivecompounds with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by HBundgaard (Elsevier, 1985), the disclosure of which is incorporatedherein by reference in its entirety.Some examples of prodrugs in accordance with the invention include:(i) where the compound contains a carboxylic acid functionality —(COOH),an ester thereof, for example, replacement of the hydrogen with(C₁-C₈)alkyl;(ii) where the compound contains an alcohol functionality (—OH), anether thereof, for example, replacement of the hydrogen with(C₁-C₆)alkanoyloxymethyl; and(iii) where the compound contains a primary or secondary aminofunctionality (—NH₂ or —NHR where R≠H), an amide thereof, for example,replacement of one or both hydrogens with (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Finally, certain inventive compounds may themselves act as prodrugs ofother of the inventive compounds.

Compounds of the invention containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Where the compoundsaccording to this invention have at least one chiral center, they mayaccordingly exist as enantiomers. Where the compounds possess two ormore chiral centers, they may additionally exist as diastereomers.Similarly, where a compound of the invention contains a cyclopropylgroup or other cyclic group where chirality exists, and alkenyl oralkenylene group, geometric cis/trans (or Z/E) isomers are possible.Where the compound contains, for example, a keto or oxime group or anaromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. Asingle compound may exhibit more than one type of isomerism.

Included within the scope of the invention are all stereoisomers,geometric isomers and tautomeric forms of the inventive compounds,including compounds exhibiting more than one type of isomerism, andmixtures of one or more thereof. Also included are acid addition or basesalts wherein the counterion is optically active, for example, D-lactateor L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC) or supercritical fluid chromatography (SFC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound contains an acidic or basic moiety, an acidor base such as tartaric acid or 1-phenylethylamine.

The resulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to one skilled in the art.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art; see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosureof which is incorporated herein by reference in its entirety.

The invention also includes isotopically-labeled compounds of theinvention, wherein one or more atoms is replaced by an atom having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopessuitable for inclusion in the compounds of the invention includeisotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³Iand ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certainisotopically-labeled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, ³H, andcarbon-14, ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection. Substitutionwith heavier isotopes such as deuterium, ²H, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products, or mixtures thereof.They may be obtained, for example, as solid plugs, powders, or films bymethods such as precipitation, crystallization, freeze drying, spraydrying, or evaporative drying. Microwave or radio frequency drying maybe used for this purpose.

The compounds can be administered alone or in combination with one ormore other compounds of the invention. Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term “excipient” is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe invention and methods for their preparation will be readily apparentto those skilled in the art. Such compositions and methods for theirpreparation can be found, for example, in ‘Remington's PharmaceuticalSciences’, 19th Edition (Mack Publishing Company, 1995), the disclosureof which is incorporated herein by reference in its entirety.

Oral Administration: The compounds of the invention may be administeredorally. Oral administration may involve swallowing, so that the compoundenters the gastrointestinal tract, or buccal or sublingualadministration may be employed by which the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films (including muco-adhesive), ovules,sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be used as fillers in soft or hard capsules andtypically include a carrier, for example, water, ethanol, polyethyleneglycol, propylene glycol, methylcellulose, or a suitable oil, and one ormore emulsifying agents and/or suspending agents. Liquid formulationsmay also be prepared by the reconstitution of a solid, for example, froma sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001), the disclosure of which is incorporated herein by reference inits entirety.

For tablet dosage forms, depending on dose, the drug may make up from 1wt % to 80 wt % of the dosage form, more typically from 5 wt % to 60 wt% of the dosage form. In addition to the drug, tablets generally containa disintegrant. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinized starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents are typically inamounts of from 0.2 wt % to 5 wt % of the tablet, and glidants typicallyfrom 0.2 wt % to 1 wt % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallyare present in amounts from 0.25 wt % to 10 wt %, preferably from 0.5 wt% to 3 wt % of the tablet.

Other conventional ingredients include anti-oxidants, colorants,flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80 wt % drug, from about 10 wt %to about 90 wt % binder, from about 0 wt % to about 85 wt % diluent,from about 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt% to about 10 wt % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tableting. The finalformulation may include one or more layers and may be coated oruncoated; or encapsulated.

The formulation of tablets is discussed in detail in “PharmaceuticalDosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, MarcelDekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of whichis incorporated herein by reference in its entirety.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations are described in U.S. Pat. No.6,106,864. Details of other suitable release technologies such as highenergy dispersions and osmotic and coated particles can be found inVerma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). Theuse of chewing gum to achieve controlled release is described in WO00/35298. The disclosures of these references are incorporated herein byreference in their entireties.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilization, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents. Formulations for parenteral administrationmay be formulated to be immediate and/or modified release. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release. Thus compounds of the invention may beformulated as a solid, semi-solid, or thixotropic liquid foradministration as an implanted depot providing modified release of theactive compound. Examples of such formulations include drug-coatedstents and PGLA microspheres.

Topical Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibers, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may be incorporated;see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan(October 1999). Other means of topical administration include deliveryby electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Thedisclosures of these references are incorporated herein by reference intheir entireties.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Inhaled/Intranasal Administration

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may include a bioadhesive agent, for example,chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilizing, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronized to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the compound of the invention, a suitable powderbase such as lactose or starch and a performance modifier such asl-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate, preferably the latter. Other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μL to 100 μL. A typical formulation includes acompound of the invention, propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example,poly(DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing a desired mount of the compound of theinvention. The overall daily dose may be administered in a single doseor, more usually, as divided doses throughout the day.

Rectal/Intravaginal Administration: Compounds of the invention may beadministered rectally or vaginally, for example, in the form of asuppository, pessary, or enema. Cocoa butter is a traditionalsuppository base, but various alternatives may be used as appropriate.Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release.Modified release formulations include delayed-, sustained-, pulsed-,controlled-, targeted and programmed release.Ocular Administration: Compounds of the invention may also beadministered directly to the eye or ear, typically in the form of dropsof a micronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g. absorbable gel sponges, collagen)and non-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

Other Technologies

Compounds of the invention may be combined with soluble macromolecularentities, such as cyclodextrin and suitable derivatives thereof orpolyethylene glycol-containing polymers, in order to improve theirsolubility, dissolution rate, taste-masking, bioavailability and/orstability for use in any of the aforementioned modes of administration.Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubilizer. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518and WO 98/55148, the disclosures of which are incorporated herein byreference in their entireties.Dosage: The amount of the active compound administered will be dependenton the subject being treated, the severity of the disorder or condition,the rate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage istypically in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 0.01 to about 35 mg/kg/day, in single ordivided doses. For a 70 kg human, this would amount to about 0.07 toabout 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe used without causing any harmful side effect, with such larger dosestypically divided into several smaller doses for administrationthroughout the day.Kit-of-Parts: Inasmuch as it may desirable to administer a combinationof active compounds, for example, for the purpose of treating aparticular disease or condition, it is within the scope of the presentinvention that two or more pharmaceutical compositions, at least one ofwhich contains a compound in accordance with the invention, mayconveniently be combined in the form of a kit suitable forcoadministration of the compositions. Thus the kit of the inventionincludes two or more separate pharmaceutical compositions, at least oneof which contains a compound of the invention, and means for separatelyretaining said compositions, such as a container, divided bottle, ordivided foil packet. An example of such a kit is the familiar blisterpack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically includes directions foradministration and may be provided with a memory aid.

EXAMPLES

For some of the steps described it may be necessary to protect potentialreactive functions that are not wished to react, and to cleave saidprotecting groups in consequence. In such a case, any compatibleprotecting radical may be used. In particular methods of protection anddeprotection such as those described by T. W. Greene (Protective Groupsin Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P.J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), may beused.

All of the reactions herein and the preparations of novel startingmaterials used herein are conventional and appropriate reagents andreaction conditions for their performance or preparation as well asprocedures for isolating the desired products will be well-known tothose skilled in the art with reference to literature precedents and theexamples and preparations hereto.

The following abbreviations may be used herein:

Ac (acetyl); AcCl (acetyl chloride); AcOH or HOAc (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); Boc or boc (tert-butoxycarbonyl); ca.(about or approximately); CDCl₃ (deuterated chloroform); CH₂Cl₂ and/orDCM (dichloromethane); DAST (Diethylaminosulfur trifluoride); DCE(dichloroethane); DEA (diethylamine); DIBAL or DIBAL-H(diisobutylaluminum hydride); DIC (diisopropylcarbodiimide); DIPEA orHunig's base (N,N-diisopropylethylamine); DMA (dimethylacetamide); DMF(dimethylformamide); DME (ethylene glycol); DMP (Dess-MartinPeriodinane); DMAP (4-dimethylaminopyridine); DMSO (dimethylsulfoxide);DMSO-d₆ (deuterated dimethylsulfoxide); EDC or EDCl(1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide); Et (ethyl); Et₃N orTEA (triethylamine); EtOH (ethanol); EtOAc (ethyl acetate); Et₂O(diethyl ether); g or gm (gram or grams); HATU(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); HBTU(o-(benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate);HMPT (Tris(dimethylamino)phosphine); HPLC (high-performance liquidchromatography); HOBT (1-hydroxy benzotriazole); h or hr (hour or hours,as appropriate); iBu (isobutyl); IPA (iso-propyl alcohol); iPr(isopropyl); iPrOAc (isopropyl acetate); KHMDS (potassiumbis(trimethylsilyl)amide); KOAc (potassium acetate); LCMS (liquidchromatography-mass spectrometry); LiHMDS (lithiumbis(trimethylsilyl)amide); Me (methyl); MeOH (methanol); MeOD(deuterated methanol); MeCN (acetonitrile); m or min (minute or minutes,as appropriate); mg (milligram or milligrams); Ms (methylsulfonyl); MsCl(methanesulfonyl chloride); N (normal); NBS (N-Bromosuccinimide); NFSI(N-Fluorodibenzenesulfonimide); NMR (nuclear magnetic resonance); nBu(n-butyl); nBuLi (n-butyl lithium); nPr (n-propyl); Pd/C (palladium oncarbon); Pd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(O));Pd(dppf)Cl₂([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Ph(phenyl); PTSA or pTSA (p-Toluene sulfonic acid); Rt (retention time);rt (room temperature); RuCl(p-cymene)[(R,R)-Ts-DPEN]([N-[(1R,2R)-2-(Amino-KN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-KN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium);s or sec (second or seconds, as appropriate); Selectfluor(N-Chloromethyl-N′-fluorotriethylenediammonium bis(tetrafluoroborate));SEM (2-Trimethylsilylethoxymethoxy); SFC (supercritical fluidchromatography); Si-Thiol (silica 1-propanethiol); T3P (propylphosphonicanhydride); TBAF (tetrabutyl ammonium fluoride); TBDMSCl(t-butyl-dimethylsilyl chloride); TBME or MTBE (terf-butyl methylether); t-BuOH (2-methyl-2-propanol, tert-butanol or tert-butylalcohol); TDA-1 (Tris[2-(2-methoxyethoxy)ethyl]amine orTris(3,6-dioxaheptyl)amine); TEA, NEt₃ or Et₃N (triethylamine); TFA(trifluoroacetic acid); THF (tetrahydrofuran); THP (tetrahydropyran);TLC (thin layer chromatography); TMS (trimethylsilyl); TMSCl(trimethylsilyl chloride); TMSCF₃ (Trimethyl(trifluoromethyl)silane);Tos or tosyl (4-toluenesulfonyl); TOSMIC (p-Toluenesulfonylmethylisocyanide); UV (ultraviolet).

General Synthetic Scheme for Carbonucleoside Compounds

As exemplified in Scheme 1, a compound such as 1a can be purchased orsynthesized (Chem. Rev., 2012, 112 (8), pp 4642-4686). Typically, methyl(1S,2R,3S,4R)-4-amino-2,3-dihydroxycyclopentane-1-carboxylate can reactwith an appropriately functionalized pyrimidine or other heterocycle togive compounds such as 1b. This reaction can be accomplished throughstandard nucleophilic aromatic substitution using conditions such asdiisopropylethylamine or trimethylamine in DMSO, DMA or DMF orconditions using cesium fluoride in DMSO. Alternative reaction conditionmay include metal coupling reactions such as palladium couplings.Cyclization of compounds such as 1b to compounds such as 1c can occurunder a variety of conditions including condensations or metal couplingsdepending on the atom type of A. Protection of the diol to produce 1dcan be done using acetone or 2,2-dimethoxypropane in mild acid. Esterssuch as 1d are converted into alkyl and aryl ketones such as 1e usingalkyl and aryl metal reagents such as alkyl and aryl Grignards (M=Mg),alkyl and aryl lithium reagents, alkyl and aryl cuprates, alkyl and arylzincates as well as other organometal reagents. Typically thesereactions are run in ethereal solvents such as THF, MeTHF, dioxane orsimilar solvent at temperatures ranging from −78° C. to 60° C. Alkyl andaryl ketones such as 1e can be converted to secondary alcohols such as1f using reducing reagents such as NaBH4, LiBH4, LiAIH4, DIBAL andothers. Typically these reactions can be run in a variety of solventssuch as DCM, THF, MeOH, EtOH or others at varying temperatures. Alkyland aryl ketones such as 1e can be preferentially converted todiastereomerically enriched secondary alcohols such as 1f using chiralreducing conditions such as RuCl(p-cymene)[(R,R)-Ts-DPEN] and sodiumformate (J. Org. Chem, 2014, 79, 3238-3243). Typically, these reactionsare done in EtOAc solvent and run at room temperature. Finally,compounds such as 1f can be deprotected to reveal the triol compoundssuch as 1g by treatment with acid such as TFA or dilute HCl. Typicallythese reactions are done in the presence of water at 0° C. or rt.Compounds at every step may be purified by standard techniques such ascolumn chromatography, crystallization, reverse phase HPLC or SFC. Ifnecessary, separation of the diastereomers of 1f or 1g may be carriedout under standard methods known in the art such as chiral SFC or HPLCto afford single diastereomers.

As exemplified in Scheme 2, compounds such as 1d can be hydrolyzed withbase to give the acid 2a. Typically these reactions are run using somehydroxide source such as lithium hydroxide, sodium hydroxide or other.Compounds similar to the carboxylic acid 2a are converted to compoundssuch as the Weinreb amide 2b via treatment withN,O-dimethylhydroxylamine HCl and standard amide coupling reagents suchas HOBT and EDCl, T3P or HATU with a base such as DIPEA or TEA.Typically, these reactions are done in solvents such as DMF or THF andrun at temperatures ranging from 0° C. to 60° C. Weinreb amides such as2b are converted into alkyl and aryl ketones such as 1e using alkyl andaryl metal reagents such as alkyl and aryl Grignards (M=Mg), alkyl andaryl lithium reagents, alkyl and aryl cuprates, alkyl and aryl zincatesas well as other organometal reagents. Typically these reactions are runin ethereal solvents such as THF, MeTHF, dioxane or similar solvent attemperatures ranging from −78° C. to 60° C.

As exemplified in Scheme 3, a compound such as 3a[(3aS,4R,7S,7aR)-2,2-dimethyltetrahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridin-6(3aH)-one]can be purchased or synthesized (Chem. Rev., 2012, 112 (8), 4642-4686)and can be protected as the carbamate using reagents such as Bocanhydride or benzoyl chloride resulting in lactams such as 3b. Theseactivated lactams (3b) are converted into alkyl and aryl ketones such as3c using alkyl and aryl metal reagents such as alkyl and aryl Grignards(M=Mg), alkyl and aryl lithium reagents, alkyl and aryl cuprates, alkyland aryl zincates as well as other organometal reagents. Typically thesereactions are run in ethereal solvents such as THF, MeTHF, dioxane orsimilar solvent at temperatures ranging from −78° C. to 60° C. Alkyl andaryl ketones such as 3c can be converted to secondary alcohols such as3d using reducing reagents such as NaBH4, LiBH4, LiAIH4, DIBAL andothers. Typically these reactions can be run in a variety of solventssuch as DCM, THF, MeOH, EtOH or others at varying temperatures. Alkyland aryl ketones such as 3c can be preferentially converted todiastereomerically enriched secondary alcohols such as 3d using chiralreducing conditions such as RuCl(p-cymene)[(S,S)-Ts-DPEN] and sodiumformate (J. Org. Chem, 2014, 79, 3238-3243). Typically, these reactionsare done in EtOAc solvent and run at room temperature. The resultingsecondary alcohol such as 3d can be protected with a variety of reagentsthat provide orthogonal deprotection strategies to the carbamateinstalled earlier in the route. Such reagents include TMSCl, TESCl,TBDMSCl, TIPSCl, as well as others. Compounds such as 3e can bedeprotected to give compounds such as 3f through a variety of methodsdepending on what carbamate is installed. Examples include using dilutetrifluoroacetic acid solution in the case of Boc carbamate orhydrogenolysis with Pd catalyst and hydrogen gas in the case of benzoylcarbamate. Compounds such as 3f can react with appropriately substitutedheterocycles in a nucleophilic aromatic substitution to yield compoundssuch as 3g. Such reactions are usually accomplished using organic basessuch as diisopropylethylamine or trimethylamine in DMSO, DMA or DMF orconditions using cesium fluoride in DMSO. Alternative reaction conditionmay include metal coupling reactions such as palladium couplings.Cyclization of compounds such as 3g to compounds such as 3h can occurunder a variety of conditions including condensations or metal couplingsdepending on the atom type of A. Finally, compounds such as 3h can bedeprotected to reveal the triol compounds such as 3i by treatment withacid such as TFA or dilute HCl. Typically these reactions are done inthe presence of water at 0° C. or rt. Compounds at every step may bepurified by standard techniques such as column chromatography,crystallization, reverse phase HPLC or SFC. If necessary, separation ofthe diastereomers of 3d or any compound afterwards may be carried outunder standard methods known in the art such as chiral SFC or HPLC toafford single diastereomers.

As exemplified in Scheme 4, a compound such as 4a[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol]can be purchased or synthesizesd [J. Perkin Trans. I, 1985, 1437;Tetrahedron Letters, 2000, (41) 9537-9530]. Compounds such as 4a canundergo nucleophilic aromatic substitution with the appropriatelysubstituted heterocycle to yield compounds such as 4b. Cyclization ofcompounds such as 4b to compounds such as 4c can occur under a varietyof conditions including condensations or metal couplings depending onthe atom type of A. Compounds such as 4c can undergo nucleophilicaromatic substitution with the appropriately substituted fluorobenzeneto yield phenol ethers such as 4d. Finally, compounds such as 4d can bedeprotected to reveal the diol compounds such as 4e by treatment withacid such as TFA or dilute HCl. Typically these reactions are done inthe presence of water at 0° C. or rt. Compounds at every step may bepurified by standard techniques such as column chromatography,crystallization, reverse phase HPLC or SFC. If necessary, separation ofthe diastereomers of 4a or any compound afterwards may be carried outunder standard methods known in the art such as chiral SFC or HPLC toafford single diastereomers.

As exemplified in Scheme 5, compounds such as 5a can be purchased orsynthesized (Chemical Science, 2010, 1, p 427; Journal of the AmericanChemical Society, 2000, 122, p5947; Organic Letters, 2012, 14(9), p2254). Compounds such as 5a can undergo asymmetric allylic alkylationwith appropriately substituted heterocycles using a variety of palladiumcatalysts and chiral ligands to form compounds such as 5b. Compoundssuch as 5b can undergo allylic alkylation with appropriately substitutedphenols or hydroxyheterocycles using a variety of palladium catalystsand ligands to form compounds such as 5c. Compounds such as 5c can bedihydroxylated to form diols such as 5d using reagents such as osmiumtertroxide or potassium permanganate. Compounds at every step may bepurified by standard techniques such as column chromatography,crystallization, reverse phase HPLC or SFC. If necessary, separation ofthe diastereomers of 5d may be carried out under standard methods knownin the art such as chiral SFC or HPLC to afford single diastereomers.

As exemplified in Scheme 6, compounds such as 5a can undergo asymmetricallylic alkylation with appropriately substituted phenols orhydroxyheterocycles using a variety of palladium catalysts and chiralligands to form compounds such as 6a. Compounds such as 6a can undergoallylic alkylation with appropriately substituted heterocycles using avariety of palladium catalysts and ligands to form compounds such as 5c.Compounds such as 5c can be dihydroxylated to form diols such as 5dusing reagents such as osmium tertroxide or potassium permanganate.

As exemplified in Scheme 7, compounds such as 5b can be hydrolyzed tocompounds such as 7a using some hydroxide source such as lithiumhydroxide, sodium hydroxide or other. Compounds such as 7a can undergonucleophilic aromatic substitution with the appropriately substitutedheterocycle to yield compounds such as 7b. Compounds such as 7b can bedihydroxylated to form diols such as 7c using reagents such as osmiumtertroxide or potassium permanganate. Compounds at every step may bepurified by standard techniques such as column chromatography,crystallization, reverse phase HPLC or SFC. If necessary, separation ofthe diastereomers of 7c may be carried out under standard methods knownin the art such as chiral SFC or HPLC to afford single diastereomers.

As exemplified in Scheme 8; compounds such as 6a can be hydrolyzed tocompounds such as 8a using some hydroxide source such as lithiumhydroxide, sodium hydroxide or other. Compounds such as 8a can undergonucleophilic aromatic substitution with the appropriately substitutedheterocycle to yield compounds such as 8b. Compounds such as 8b can bedihydroxylated to form diols such as 8c using reagents such as osmiumtertroxide or potassium permanganate. Compounds at every step may bepurified by standard techniques such as column chromatography,crystallization, reverse phase HPLC or SFC. If necessary, separation ofthe diastereomers of 8c may be carried out under standard methods knownin the art such as chiral SFC or HPLC to afford single diastereomers.

Example 1 (Scheme A): Synthesis of(1S,2R,3R,5R)-3-((R)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(A-12) Example 2 (Scheme A): Synthesis of(1S,2R,3R,5R)-3-((S)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(A-13)

Step 1: Synthesis of(1R,4S,5R,6S)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one (A-2)

To a light yellow bi-phasic mixture of(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one A-1 (Chemical Reviews, 2012,112 (8), pp 4642-4686) (100 g, 916 mmol) and NMO (118 g, 1.01 mol) inisoamyl alcohol (500 mL) and water (500 mL) was added 2.5% OsO₄ int-BuOH (1.5 g, 5.9 mmol, 76 mL) at rt (15° C.). The mixture was heatedat 70° C. for 2 hrs. The mixture was cooled to rt (15° C.). NaHSO₃ (12g) was added and stirred at rt (15° C.) for 45 min. The mixture wasconcentrated in vacuo to afford crude (150 g) as dark solid which waspurified by silica gel chromatography eluted with MeOH in DCM=10% toafford A-2 (90 g, 69%) as a light pink solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.54 (br. s., 1H), 5.00 (dd, J=21.3, 22.6 Hz, 2H), 3.81-3.64 (m,2H), 3.43 (s, 1H), 2.25 (s, 1H), 1.93-1.67 (m, 2H)

Step 2: Synthesis of methyl(1S,2R,3S,4R)-4-amino-2,3-dihydroxycyclopentane-1-carboxylate-HCl (A-3)

Compound A-2 (33 g, 231 mmol) was added to 4N HCl in MeOH (500 mL) at rt(15° C.). The suspension was stirred at rt (15° C.) for 20 hrs. Themixture was concentrated in vacuo and the residue was suspended in DCMand filtered. The solid was washed with DCM and dried in vacuo to affordA-3 (45 g, 92%) as a white solid. LCMS [M+1] 176; ¹H NMR (400 MHz, D₂O)δ ppm 4.27 (t, J=5.1 Hz, 1H), 4.04 (t, J=6.4 Hz, 1H), 3.72 (s, 3H), 3.55(q, J=8.4 Hz, 1H), 2.97 (dt, J=5.0, 8.8 Hz, 1H), 2.49 (td, J=8.5, 13.8Hz, 1H), 1.83 (td, J=9.2, 13.7 Hz, 1H)

Step 3: Synthesis of methyl(1S,2R,3S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentane-1-carboxylate(A-4)

To a white suspension compound A-3 (42 g, 200 mmol) and2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (40 g, 209 mmol) in EtOH (400mL) was added Et₃N (40.4 g, 400 mmol). The resulting yellow solution wasstirred at reflux for 2 hrs. The mixture was concentrated in vacuo toabout 100 mL. The residue was poured into NH₄Cl aq (500 mL) andextracted with EtOAc (200 mL×3). The extract was washed with brine (200mL), dried over Na₂SO₄ and concentrated in vacuo to afford crude A-4 (60g, >99%) as a red gum which was used in the next step directly. LCMS[M+1] 312

Step 4: Synthesis of methyl(3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate(A-5)

To a solution of crude compound A-4 (60 g, 192 mmol) in2,2-dimethoxypropane (300 mL) and acetone (300 mL) was added TsOH.H₂O(40 g, 212 mmol). The mixture was stirred at rt (15° C.) for 1 hr. Themixture was poured into NaHCO₃ aq (1000 mL) and extracted with EtOAc(500 mL). The extract was washed with brine, concentrated in vacuo toafford crude material which was purified by silica gel chromatographyeluted with EtOAc in petroleum ether from 0-100% to afford A-5 (42 g,62%) as a yellow gum which solidified upon standing. LCMS [M+1] 352; ¹HNMR (400 MHz, CDCl₃) δ ppm 8.63 (s, 1H), 7.29 (d, J=3.5 Hz, 1H), 6.64(d, J=3.8 Hz, 1H), 5.15-5.04 (m, 2H), 5.03-4.98 (m, 1H), 3.76 (s, 3H),3.12 (ddd, J=5.3, 7.6, 10.7 Hz, 1H), 2.75-2.59 (m, 2H), 1.59 (s, 3H),1.33 (s, 3H)

Step 5: Synthesis of methyl(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate(A-6)

To a solution of A-5 (15 g, 42.6 mmol) in dry THF (125 mL) was addedPd(PPh₃)₄(1.97 g, 1.71 mmol). To the resulting yellow solution was added1M solution of Zn(Me)₂ (171 mL, 171 mmol). The mixture was degassed withN₂ four times. The yellow solution was heated at reflux for 3 hrs whichchanged to a dark solution. The mixture was poured into cooled NH₄Cl aq(200 mL) carefully and extracted with EtOAc (200 mL×3). The extract waswashed with brine (200 mL), dried over Na₂SO₄ and concentrated in vacuoto afford crude (18 g) as a yellow gum. The crude material was purifiedby silica gel chromatography eluted with EtOAc in petroleum ether from 0to 100% to A-6 (13.5 g, 96%) as a yellow gum. [α]²⁰ _(D) −21.57° (c=8.4mg/mL, methanol). LCMS [M+1] 332; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.65(s, 1H), 7.74 (d, J=3.5 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H), 5.18-5.06 (m,1H), 5.01-4.90 (m, 2H), 3.65 (s, 3H), 3.15-3.03 (m, 1H), 2.64 (s, 3H),2.46-2.40 (m, 1H), 1.49 (s, 3H), 1.23 (s, 3H)

Step 6: Synthesis of(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylicacid (A-7)

A mixture of A-6 (13 g, 33 mmol) and LiOH (2.8 g, 66.7 mmol) in THF (100mL)/H₂O (100 mL) was stirred at rt (15° C.) for 4 hrs. TLC(DCM/MeOH=10/1) showed most of SM was consumed. The mixture was dilutedwith water (50 mL) and washed with EtOAc (100 mL×2). To the aqueouslayer was added H₃PO₄ (3.6 g, 37 mmol) and extracted with EtOAc/THF (50mL/50 mL×5). The extract was dried over Na₂SO₄ and concentrated in vacuoto afford A-7 (8.9 g, 84%) as a yellow solid. LCMS [M+1] 318; ¹H NMR(400 MHz, CDCl₃) δ ppm 8.77 (s, 1H), 7.26 (br. s, 1H), 6.59 (d, J=3.8Hz, 1H), 5.25 (t, J=5.3 Hz, 1H), 5.14-4.98 (m, 2H), 3.18 (ddd, J=4.8,7.8, 10.0 Hz, 1H), 2.77-2.60 (m, 5H), 1.60 (s, 3H), 1.35 (s, 3H)

Step 7: Synthesis of(3aR,4S,6R,6aS)—N-methoxy-N,2,2-trimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxamide(A-8)

To a suspension of crude A-7 (7 g, 22.1 mmol) andN,O-dimethylhydroxylamine-HCl (4.30 g, 44.1 mmol) in THF (140 mL) wasadded DIPEA (11.4 g, 88.2 mmol) and 50% T3P (28.1 g, 25.8 mL, 44.1 mmol)at rt (15° C.). The resulting red solution was stirred at rt (15° C.)for 20 hrs.

LCMS showed the main peak was desired compound. The mixture was dilutedwith EtOAc and washed with NH₄Cl aq, NaHCO₃ aq, brine, dried over Na₂SO₄and concentrated in vacuo to A-8 (7.3 g, 91.8%) as a yellow gum. [α]²⁰_(D) +27.30° (c=2.82 mg/mL, methanol); LCMS [M+1] 361; ¹H NMR (400 MHz,CDCl₃) δ ppm 8.77 (s, 1H), 7.31 (d, J=3.5 Hz, 1H), 6.60 (d, J=3.5 Hz,1H), 5.36-5.27 (m, 1H), 5.11-5.03 (m, 1H), 4.91 (dd, J=5.6, 7.2 Hz, 1H),3.77 (s, 3H), 3.61-3.51 (m, 1H), 3.24 (s, 3H), 2.72 (s, 3H), 2.65-2.56(m, 1H), 2.54-2.42 (m, 1H), 1.60 (s, 3H), 1.30 (s, 3H)

Step 8: Synthesis of1-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)ethan-1-one(A-9)

To a light yellow solution of A-8 (130 mg, 0.361 mmol) in THF (5.39 mL)was added MeMgBr (3.0 M solution in diethyl ether, 0.144 mL, 0.433 mmol)at 0° C. After the addition, the mixture was stirred at 0° C. for 40min. The mixture was quenched with aq.NH₄Cl (40 mL) in an ice bath andextracted with EtOAc (30 mL×2). The extract was washed with brine (20mL), dried over Na₂SO₄ and concentrated in vacuo to afford crudecompound A-9 (110 mg, 97%) as a yellow oil and used as is in the nextstep.

Step 9: Synthesis of(R)-1-((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)ethan-1-ol(A-10) and(S)-1-((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)ethan-1-ol(A-11)

To a yellow solution of A-9 (110 mg, 0.349 mmol) in dry MeOH (6 mL) wasadded NaBH₄ (26 mg, 0.698 mmol) at 0° C. After addition, the mixture wasstirred at 0° C. for 60 min. Then the reaction mixture was concentratedin vacuum to give a white solid (150 mg) which was separated by chiralSFC to give A-10 (62 mg, 56%) and A-11 (61 mg, 55%) and used as is.

Step 10: Synthesis of(1S,2R,3R,5R)-3-((R)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(A-12) and(1S,2R,3R,5R)-3-((S)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(A-13)

To a yellow suspension of A-10 (74 mg, 0.02 mmol) in H₂O (1 mL) wasadded TFA (1 mL) at 0° C. The mixture was stirred at room temperature(15° C.) for 2 hrs. Saturated aqueous K₂CO₃ (10 mL) was added into themixture (0° C.) slowly until the pH 7-8. Purify by prep HPLC to givecompound A-12 (34 mg, 53%). LCMS [M+1] 278; ¹H NMR (400 MHz, MeOD-d₄) δppm 8.60 (s, 1H), 7.60 (d, J=3.8 Hz, 1H), 6.73 (d, J=3.5 Hz, 1H),5.12-5.00 (m, 1H), 4.37 (dd, J=5.8, 9.3 Hz, 1H), 4.17 (dd, J=2.9, 5.6Hz, 1H), 3.81 (quin, J=6.2 Hz, 1H), 2.71 (s, 3H), 2.31 (td, J=8.3, 12.7Hz, 1H), 2.07 (ddt, J=2.8, 5.9, 9.0 Hz, 1H), 1.84 (ddd, J=9.3, 10.9,12.7 Hz, 1H), 1.26 (d, J=6.3 Hz, 3H)

To a yellow suspension of A-11 (74 mg, 0.23 mmol) in H₂O (1.5 mL) wasadded TFA (1.5 mL) drop-wise at 0° C. Then the reaction mixture wasstirred at room temperature (20° C.) for 2 hrs, then adjusted to pH=7with 20% K₂CO₃. The aqueous phase was purified by prep HPLC to give A-13(45 mg, 70%). LCMS [M+1] 278; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.59 (s,1H), 7.61 (d, J=3.53 Hz, 1H), 6.72 (d, J=3.53 Hz, 1H), 5.03-5.12 (m,1H), 3.92-4.30 (dd, J=8.60, 5.95 Hz, 1H), 3.92-4.03 (m, 2H), 2.70 (s,3H), 2.28 (dt, J=12.57, 8.27 Hz, 1H), 2.06 (tt, J=8.71, 4.30 Hz, 1H),1.88-1.99 (m, 1H), 1.22 (d, J=6.62 Hz, 3H)

Examples 3-16 were prepared in using similar chemistry in Scheme A usingthe appropriate Grignard reagent for step 8.

Example 3: 3,4- Difluoro- phenyl magnesium bromide

375.90 [M + 1] (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.61 (s, 1 H) 7.65 (d, J = 3.74 Hz, 1 H) 7.39-7.45 (m, 1 H) 7.32-7.39(m, 1 H) 7.19-7.28 (m, 1 H) 6.70 (d, J = 3.52 Hz, 1 H) 5.69 (d, J = 4.62Hz, 1 H) 4.93- 5.02 (m, 1 H) 4.80 (br. s., 1 H) 4.51-4.64 (m, 2 H)4.23-4.35 (m, 1 H) 3.94 (d, J = 4.18 Hz, 1 H) 2.63 (s, 3 H) 2.20-2.30(m, 1 H) 2.00 (dt, J = 12.93, 8.72 Hz, 1 H) 1.60 (ddd, J = 12.87, 10.87,8.25 Hz, 1 H) Example 4: 3,4- Difluoro- phenyl magnesium bromide

375.90 [M + 1] (1S,2R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.62 (s, 1 H) 7.68 (d, J = 3.74 Hz, 1 H) 7.32-7.41 (m, 2 H) 7.14-7.23(m, 1 H) 6.73 (d, J = 3.52 Hz, 1 H) 5.68 (d, J = 4.40 Hz, 1 H) 4.90-4.98(m, 1 H) 4.86 (br. s., 1 H) 4.80 (br. s., 1 H) 4.67 (br. s., 1 H) 4.23(dd, J = 8.14, 5.72 Hz, 1 H) 3.85-3.94 (m, 1 H) 2.65 (s, 3 H) 2.23 (tt,J = 8.72, 4.37 Hz, 1 H) 1.85 (dt, J = 12.98, 8.36 Hz, 1 H) 1.78 (dt, J =12.87, 9.74 Hz, 1 H) Example 5: 3-chloro-4- fluorophenyl magnesiumbromide

391.80 [M + 1] (1S,2R,3R,5R)-3-[(S)-(3-chloro-4-fluorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.60 (s, 1 H) 7.64 (d, J = 3.52 Hz, 1 H) 7.57 (dd, J = 7.26, 1.76 Hz, 1H) 7.37-7.42 (m, 1 H) 7.32-7.37 (m, 1 H) 6.69 (d, J = 3.52 Hz, 1 H) 5.70(d, J = 4.62 Hz, 1 H) 4.93-5.02 (m, 1 H) 4.80 (d, J = 6.82 Hz, 1 H)4.58-4.62 (m, 1 H) 4.57 (d, J = 3.52 Hz, 1 H) 4.28 (dt, J = 9.57-6.00Hz, 1 H) 3.94 (br. s., 1 H) 2.63 (s, 3 H) 2.22-2.28 (m, 1 H) 2.00 (dt, J= 12.98, 8.80 Hz, 1 H) 1.60 (ddd, J = 12.87, 10.78, 8.25 Hz, 1 H)Example 6: 3-chloro-4- fluorophenyl magnesium bromide

391.85 [M + 1] (1S,2R,3R,5R)-3-[(R)-(3-chloro-4-fluorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.60 (s, 1 H) 7.66 (d, J = 3.52 Hz, 1 H) 7.52 (d, J = 6.82 Hz, 1 H),7.30-7.38 (m, 2 H) 6.71 (d, J = 3.52 Hz, 1 H) 5.68 (d, J = 4.62 Hz, 1 H)4.90-4.98 (m, 1 H) 4.86 (br. s., 1 H) 4.80 (t, J = 4.51 Hz, 1 H) 4.66(br. s., 1 H) 4.23 (br. s., 1 H) 3.88 (br. s., 1 H) 2.64 (s, 3 H)2.19-2.27 (m, 1 H) 1.86 (dt, J = 12.82, 8.45 Hz, 1 H) 1.78 (dt, J =12.87, 9.74 Hz, 1 H) Example 7: 3-chloro- phenyl magnesium bromide

373.90 [M + 1] (1S,2R,3R,5R)-3-[(S)-3-chlorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.53-8.63 (m, 1 H) 7.59-7.68 (m, 1 H) 7.44 (s, 1 H) 7.31- 7.39 (m, 2 H)7.23-7.31 (m, 1 H) 6.66-6.73 (m, 1 H) 5.66 (d, J = 4.62 Hz, 1 H)4.93-5.03 (m, 1 H) 4.79 (d, J = 6.60 Hz, 1 H) 4.57-4.62 (m, 1 H) 4.55(br. s., 1 H) 4.30 (d, J = 3.30 Hz, 1 H) 3.95 (br. s., 1 H) 2.58-2.67(m, 3 H) 2.21-2.31 (m, 1 H) 1.96-2.05 (m, 1 H) 1.55-1.67 (m, 1 H)Example 8: 3-chloro- phenyl magnesium bromide

373.80 [M + 1] (1S,2R,3R,5R)-3-[(R)-(3-chlorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.60 (s, 1 H) 7.67 (d, J = 3.74 Hz, 1 H) 7.39 (s, 1 H) 7.32- 7.37 (m, 1H) 7.29-7.32 (m, 1 H) 7.27 (d, J = 7.70 Hz, 1 H) 6.71 (d, J = 3.52 Hz, 1H) 5.65 (d, J = 4.84 Hz, 1 H) 4.90-4.98 (m, 1 H) 4.85 (br. s., 1 H) 4.81(t, J = 4.40 Hz, 1 H) 4.67 (br. s., 1 H) 4.24 (br. s., 1 H) 3.91 (br.s., 1 H) 2.64 (s, 3 H) 2.24 (dt, J = 8.47, 4.35 Hz, 1 H) 1.81-1.88 (m, 1H) 1.75-1.81 (m, 1 H) Example 9: 3-fluoro- phenyl magnesium bromide

357.85 [M + 1] (1S,2R,3R,5R)-3-[(S)-(4-fluorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d6) δ ppm8.60 (s, 1 H) 7.62 (d, J = 3.55 Hz, 1 H) 7.42 (dd, J = 8.50, 5.81 Hz, 2H) 7.13 (t, J = 8.93 Hz, 2 H) 6.68 (d, J = 3.55 Hz, 1 H) 5.51 (d, J =4.52 Hz, 1 H) 4.91- 5.05 (m, 1 H) 4.76 (d, J = 6.97 Hz, 1 H) 4.59 (dd, J= 6.79, 4.71 Hz, 1 H) 4.53 (d, J = 3.79 Hz, 1 H) 4.32 (dt, J = 9.60,6.08 Hz, 1 H) 3.99 (br. s., 1 H) 2.63 (s, 3 H) 2.26 (q, J = 7.34 Hz, 1H) 1.96 (dt, J = 12.72, 8.80 Hz, 1 H) 1.49-1.64 (m, 1 H) Example 10:3-fluoro- phenyl magnesium bromide

357.85 [M + 1] (1S,2R,3R,5R)-3-[(R)-(4-fluorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm8.57 (s, 1 H) 7.65 (d, J = 3.52 Hz, 1 H) 7.36 (t, J = 6.60 Hz, 2 H) 7.11(t, J = 8.36 Hz, 2 H) 6.73 (d, J = 3.74 Hz, 1 H) 5.70 (br. s., 1 H) 4.93(q, J = 9.02 Hz, 2 H) 4.78 (d, J = 4.40 Hz, 2 H) 4.19-4.26 (m, 2 H) 2.63(s, 3 H) 2.18-2.28 (m, 1 H) 1.86 (dt, J = 13.04, 8.45 Hz, 1 H) 1.71-1.82(m, 1 H) Example 11: 4-chloro- phenyl magnesium bromide

373.90 [M + 1] (1S,2R,3R,5R)-3-[(S)-(4-chlorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d6) δ ppm1.58 (ddd, J = 12.90, 10.64, 8.13 Hz, 1 H) 1.98 (dt, J = 12.93, 8.70 Hz,1 H) 2.20-2.29 (m, 1 H) 2.58-2.66 (m, 3 H) 3.96 (d, J = 3.79 Hz, 1 H)4.25-4.35 (m, 1 H) 4.52 (br. s., 1 H) 4.58 (d, J = 4.28 Hz, 1 H) 4.76(br. s., 1 H) 4.91-5.04 (m, 1 H) 5.57 (br. s., 1 H) 6.70 (d, J = 3.55Hz, 1 H) 7.32-7.45 (m, 4 H) 7.64 (d, J = 3.67 Hz, 1 H) 8.61 (s, 1 H)Example 12: 4-chloro- phenyl magnesium bromide

373.85 [M + 1] (1S,2R,3R,5R)-3-[(R)-(4-chlorophenyl)(hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d6) δ ppm1.73-1.92 (m, 2 H) 2.22 (tt, J = 8.67, 4.23 Hz, 1 H) 2.67 (s, 3 H)3.84-3.96 (m, 1 H) 4.24 (dd, J = 8.44, 5.50 Hz, 1 H) 4.64 (br. s., 1 H)4.73-4.89 (m, 2 H) 4.89- 5.01 (m, 1 H) 5.56 (br. s., 1 H) 6.76 (d, J =3.55 Hz, 1 H) 7.33-7.40 (m, 4 H) 7.71 (d, J = 3.55 Hz, 1 H) 8.65 (s, 1H) Example 13: 3,4,5- trifluoro- phenyl magnesium bromide

393.90 [M + 1] (1S,2R,3R,5R)-3-[(S)-hydroxy(3,4,5-trifluorophenyl)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz,DMSO-d6) δ ppm 8.53 (s, 1 H) 7.59 (d, J = 3.52 Hz, 1 H) 7.21-7.29 (m, 2H) 6.63 (d, J = 3.52 Hz, 1 H) 5.76 (d, J = 4.40 Hz, 1 H) 4.88-4.95 (m, 1H) 4.74 (d, J = 6.82 Hz, 1 H) 4.48- 4.56 (m, 2 H) 4.18 (dt, J = 9.52,6.02 Hz, 1 H) 3.84 (br. s., 1 H) 2.56 (s, 2 H) 2.15-2.23 (m, 1 H) 1.97(dt, J = 12.82, 8.67 Hz, 1 H) 1.57 (ddd, J = 12.60, 10.95, 8.58 Hz, 1 H)Example 14: 3,4,5- trifluoro- phenyl magnesium bromide

393.90 [M + 1] (1S,2R,3R,5R)-3-[(R)-hydroxy(3,4,5-trifluorophenyl)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H)7.58 (d, J = 3.52 Hz, 1 H) 7.21 (dd, J = 8.69, 6.93 Hz, 2 H) 6.64 (d, J= 3.52 Hz, 1 H) 5.75 (d, J = 4.84 Hz, 1 H) 4.86 (dt, J = 10.07, 8.39 Hz,1 H) 4.81 (d, J = 6.60 Hz, 1 H) 4.75 (t, J = 4.62 Hz, 1 H) 4.61 (d, J =4.62 Hz, 1 H) 4.15 (dt, J = 8.14, 6.16 Hz, 1 H) 3.85 (q, J = 4.40 Hz, 1H) 2.57 (s, 2 H) 2.17 (dq, J = 8.80, 4.40 Hz, 1 H) 1.77 (dt, J = 12.98,8.36 Hz, 1 H) 1.69 (dt, J = 12.87, 9.85 Hz, 1 H)

Synthesis of (3,4,5-trifluorophenyl)magnesium bromide (for Example 13 &14)

To a mixture of magnesium (264 mg, 11.0 mmol) and THF (5 mL) was addediodine (5.0 mg) and a solution of 5-bromo-1,2,3-trifluorobenzene (211mg, 1 mmol) in THF (0.5 mL). The mixture was heated to 60° C., and asolution of 5-bromo-1,2,3-trifluorobenzene (1.9 g, 9 mmol) in THF (4.5mL) was added by dropwise. The reaction was heated for two hours, thesolution was cooled to room temperature and used directly in the nextstep.

Examples 15 & 16 (Scheme B) were prepared in using similar chemistry inScheme A using 2,6-dimethylpyridine and nBuLi in Step 8 in place ofmethylmagnesium bromide.

To a solution of 2.6-dimethyl pyridine (168 mg, 1.56 mmol) in dry THF (8mL) at −75° C. was added n-BuLi (125 mg, 1.96 mmol, 1.22 mL, 1.6 M)dropwise, the temperature was maintained at about −70° C. The resultingsuspension was stirred at −75° C. for 1 hr. A solution of A-8 (282 mg,0.782 mmol) in dry THF (4 mL) was added at −75° C. dropwise. Theresulting suspension was stirred at −75° C. and allowed to warm to r.t.and stirred overnight. THF was evaporated, the crude product was addedH₂O and extracted with EtOAc, concentrated, purified by columnchromatography with 5% MeOH/EtOAc to give 169 mg of B-1 (53% yield) as ayellow oil. LCMS [M+1] 407.15.

Example 15

368.90 [M + 1](1S,2R,3R,5R)-3-[1-hydroxy-2-(6-methylpyridin-2-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1,2-diol ¹HNMR (700 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H) 7.60 (d, J = 3.52 Hz, 1 H)7.52 (t, J = 7.70 Hz, 1 H) 7.00 (d, J = 7.70 Hz, 1 H) 7.01 (d, J = 7.48Hz, 1 H) 6.65 (d, J = 3.30 Hz, 1 H) 4.98-5.02 (m, 1 H) 4.92 (q, J = 8.80Hz, 1 H) 4.73 (d, J = 5.72 Hz, 1 H) 4.66 (d, J = 3.08 Hz, 1 H) 4.06-4.12(m, 1 H) 4.03 (dt, J = 11.33, 5.56 Hz, 1 H) 3.83 (q, J = 4.25 Hz, 1 H)2.66- 2.75 (m, 2 H) 2.58 (s, 3 H) 2.38 (s, 3 H) 2.09 (dt, J = 12.27,8.06 Hz, 1 H) 1.84-1.89 (m, 1 H) 1.79-1.84 (m, 1 H) Example 16

368.90 [M + 1](1S,2R,3R,5R)-3-[1-hydroxy-2-(6-methylpyridin-2-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1,2-diol ¹HNMR (700 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H) 7.66 (d, J = 3.52 Hz, 1 H)7.58 (t, J = 7.70 Hz, 1 H) 7.10 (d, J = 7.48 Hz, 1 H) 7.07 (d, J = 7.48Hz, 1 H) 6.69 (d, J = 3.74 Hz, 1 H) 5.11 (d, J = 5.06 Hz, 1 H) 4.93-5.00(m, 1 H) 4.79 (d, J = 6.82 Hz, 1 H) 4.72 (d, J = 3.08 Hz, 1 H) 4.20 (dt,J = 9.19, 6.30 Hz, 1 H) 4.07-4.12 (m, 1 H) 3.85-3.90 (m, 1 H) 2.87 (dd,J = 13.64, 4.40 Hz, 1 H) 2.80 (dd, J = 13.86, 8.36 Hz, 1 H) 2.63 (s, 3H) 2.43 (s, 3 H) 2.13 (dt, J = 12.54, 8.36 Hz, 1 H) 1.95-2.03 (m, 1 H)1.68-1.76 (m, 1 H)

Example 17 (Scheme C):(1S,2R,3S,5R)-3-(1-hydroxycyclopropyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(C-2)

Step 1: Synthesis of1-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)cyclopropan-1-ol(C-1)

To a light yellow solution of A-6 (140 mg, 0.422 mmol) in dry THF (6.32mL) was added Ti(OiPr)₄ (168 mg, 0.591 mmol) and EtMgBr (3.0 M solutionin diethyl ether, 0.845 mL, 2.53 mmol) at r.t (13° C.). After addition,the mixture was stirred at 13° C. for 10 min. The mixture was quenchedwith H₂O (50 mL) in an ice bath and extracted with EtOAc (30 mL×2). Theextract was washed with brine (30 mL), dried over Na₂SO₄ andconcentrated in vacuo to afford a crude residue which was purified byflash chromatography eluted with EtOAc/DCM 0-100% to give C-1 (90 mg,65%) as a yellow solid. LCMS [M+1] 330; ¹H NMR (400 MHz, CDCl₃) δ ppm8.72 (s, 1H), 7.22 (d, J=3.5 Hz, 1H), 6.55 (d, J=3.8 Hz, 1H), 5.06-4.99(m, 1H), 4.94 (dd, J=3.3, 6.3 Hz, 1H), 4.86 (d, J=5.8 Hz, 1H), 2.74 (s,3H), 2.68-2.57 (m, 2H), 2.11 (d, J=3.0 Hz, 1H), 1.59 (s, 3H), 1.34 (s,3H), 1.25 (d, J=3.8 Hz, 1H), 0.93 (d, 1H), 0.88-0.78 (m, 1H), 0.77-0.67(m, 1H), 0.60-0.51 (m, 1H)

Step 2: Synthesis of(1S,2R,3S,5R)-3-(1-hydroxycyclopropyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(C-2)

To a suspension of C-1 (65 mg, 0.20 mmol) in H₂O (3 mL) was added TFA (3mL) at 0° C. The mixture was stirred at rt (13° C.) for 1.5 hrs. Themixture was poured into 20% K₂CO₃ aq (50 mL) and extracted with EtOAc(30 mL×3). The extract was washed with brine (50 mL×2), dried overNa₂SO₄ and concentrated in vacuo to afford C-2 (50 mg, 88%) as a solid.LCMS [M+1]290; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 1H), 7.66 (d,J=3.8 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 5.32 (s, 1H), 5.03-4.93 (m, 1H),4.77 (d, J=6.8 Hz, 1H), 4.61 (d, J=4.3 Hz, 1H), 4.19 (td, J=6.3, 8.9 Hz,1H), 4.04-3.97 (m, 1H), 2.63 (s, 3H), 2.19 (td, J=8.5, 12.8 Hz, 1H),1.93-1.82 (m, 1H), 1.63 (dt, J=3.0, 8.8 Hz, 1H), 0.67-0.60 (m, 1H),0.57-0.48 (m, 2H), 0.46-0.39 (m, 1H)

Example 18 (Scheme D):(1S,2R,3S,5R)-3-(2-hydroxypropan-2-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(D-2)

Step 1: Synthesis of2-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)propan-2-ol(D-1)

To a light yellow solution of A-6 (150 mg, 0.453 mmol) in dry THF (6.77mL) was added MeMgBr (3.0 M solution in diethyl ether, 0.905 mL, 2.72mmol) at r.t (13° C.). After addition, the mixture was stirred at 13° C.for 10 min. The mixture was quenched with H₂O (50 mL) in a ice bath andextracted with EtOAc (30 mL×2). The extract was washed with brine (30mL), dried over Na₂SO₄ and concentrated in vacuo to afford crudecompound (160 mg) as yellow oil which was purified by flashchromatography eluted with EtOAc/DCM 0-100% to give D-1 (120 mg, 80%) asa white solid. LCMS [M+1] 332; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.76 (s,1H), 7.26 (d, J=3.8 Hz, 1H), 6.57 (d, J=3.5 Hz, 1H), 5.03 (ddd, J=6.0,8.3, 10.8 Hz, 1H), 4.96-4.88 (m, 1H), 4.84 (dd, J=5.3, 7.3 Hz, 1H), 2.73(s, 3H), 2.47-2.37 (m, 2H), 2.31-2.21 (m, 1H), 1.97 (s, 1H), 1.59 (s,3H), 1.40 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H)

Step 2: Synthesis of(1S,2R,3S,5R)-3-(2-hydroxypropan-2-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(D-2)

To a suspension of D-1 (100 mg, 0.302 mmol) in H₂O (5 mL) was added TFA(5 mL) at 0° C. The mixture was stirred at rt (13° C.) for 1.5 hrs. Themixture was poured into 20% K₂CO₃ aq (50 mL) and extracted with EtOAc(30 mL×3). The extract was washed with brine (50 mL×2), dried overNa₂SO₄ and concentrated in vacuo to afford D-2 (70 mg, 80%) as a yellowsolid.

LCMS [M+1] 292; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 1H), 7.65 (d,J=3.5 Hz, 1H), 6.69 (d, J=3.5 Hz, 1H), 4.92 (dt, J=7.3, 10.4 Hz, 1H),4.73 (d, J=7.0 Hz, 1H), 4.53 (d, J=4.3 Hz, 1H), 4.32 (s, 1H), 4.08 (td,J=6.7, 9.7 Hz, 1H), 3.92 (t, J=6.3 Hz, 1H), 2.63 (s, 3H), 2.03 (td,J=7.8, 11.5 Hz, 1H), 1.88 (dt, J=2.3, 9.0 Hz, 1H), 1.84-1.73 (m, 1H),1.19 (s, 3H), 1.08 (s, 3H)

Example 19 (Scheme E): (1S,2R,3S,5R)-3-[(1S)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(E-3) Example 20 (Scheme E):(1S,2R,3S,5R)-3-[(1R)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(E-4)

Step 1: Synthesis of((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanone(E-1)

Following a similar procedure to Step 8 in Scheme A using(4-fluorophenyl)magnesium bromide gave E-1 (240 mg, 95%). LCMS [M+1]395.80. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.75 (s, 1H) 8.12 (dd,J=8.86, 5.44 Hz, 2H) 7.34 (dd, J=8.56, 5.50 Hz, 1H) 7.15-7.22 (m, 2H)6.61 (d, J=3.67 Hz, 1H) 5.28-5.37 (m, 1H) 4.98-5.08 (m, 2H) 3.71 (br.s., 1H) 2.70-2.76 (m, 4H) 2.60-2.70 (m, 1H) 1.68 (s, 3H) 1.33 (s, 3H)

Step 2: Synthesis of1-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1-(4-fluorophenyl)ethan-1-ol(E-2)

To a solution of E-1 (66 mg, 0.17 mmol) in dry THF (6.0 mL, c=0.106 M)at 50° C. was added methylmagnesium bromide (99.5 mg, 0.835 mmol, 0.278mL, 3.0 M), the resulting solution was stirred at 50° C. for 0.5 h. Themixture was added to std. NH₄Cl (20 mL) slowly, the mixture wasextracted with EtOAc (25 mL×3). The extract was washed with brine (25mL), dried over Na₂SO₄ and concentrated in vacuum to give 70 mg of E-2as a colorless oil. LCMS [M+1] 411.80.

Step 3: Synthesis of(1S,2R,3S,5R)-3-[(1S)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(E-3) and(1S,2R,3S,5R)-3-[(1R)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (E-4)

Following a similar procedure to Step 10 in Scheme A and subsequentseparation by chiral SFC gave E-3 (19 mg, 31%). LCMS [M+1] 371.90. ¹HNMR (700 MHz, DMSO-d6) δ ppm 8.61 (s, 1H) 7.61 (d, J=3.74 Hz, 1H) 7.54(dd, J=8.58, 5.72 Hz, 2H) 7.13 (t, J=8.80 Hz, 2H) 6.72 (d, J=3.52 Hz,1H) 5.26 (s, 1H) 4.97-5.06 (m, 1H) 4.70 (d, J=5.94 Hz, 1H) 4.17 (d,J=3.30 Hz, 1H) 4.04-4.12 (m, 1H) 3.54 (br. s., 1H) 2.64 (s, 3H) 2.39 (t,J=8.91 Hz, 1H) 2.19 (dt, J=12.54, 8.58 Hz, 1H) 1.95 (td, J=11.83, 8.91Hz, 1H) 1.35 (s, 3H)

and E-4 (12 mg, 19%). LCMS [M+1] 371.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm8.51-8.59 (m, 1H) 7.52-7.59 (m, 1H) 7.40-7.47 (m, 2H) 7.02-7.10 (m, 2H)6.65 (dd, J=3.52, 1.54 Hz, 1H) 5.24 (s, 1H) 4.78-4.88 (m, 2H) 4.67-4.74(m, 1H) 4.10-4.19 (m, 2H) 2.57-2.65 (m, 3H) 2.35 (t, J=9.35 Hz, 1H) 1.54(s, 3H) 1.39-1.51 (m, 2H)

Example 21 (Scheme F):(1S,2R,3S,5R)-3-[fluoro(4-fluorophenyl)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (F-3 Isomer A) Example 22 (SchemeF):(1S,2R,3S,5R)-3-[fluoro(4-fluorophenyl)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (F-4 Isomer B)

Step 1: Synthesis of((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanol(F-1)

Following a similar procedure to Step 8 in Scheme A gave F-1 (110 mg,99%). LCMS [M+1]398.15.

Step 2: Synthesis of7-((3aS,4R,6S,6aR)-6-(fluoro(4-fluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine(F-2)

To a solution of F-1 (110 mg, 0.277 mmol) in 5 mL DCM was added DAST(223 mg, 1.38 mmol), stirred at r.t. for 30 min. The reaction wasquenched with std. NaHCO₃, the phases were separated and the aqueousphase was extracted with 3 portions of DCM. The organic phases werecombined and washed with brine, concentrated to give crude F-2 which wasused directly for next step. LCMS [M+1] 400.10.

Step 3: Synthesis of(1S,2R,3S,5R)-3-[fluoro(4-fluorophenyl)methyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol

Following a similar procedure to Step 10 in Scheme A and subsequentseparation by chiral SFC gave

F-3 Isomer A (7.7 mg, 7.8% two steps)

LCMS [M+1] 360.10. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.40-1.49 (m, 1H)1.91 (dt, J=12.87, 8.64 Hz, 1H) 2.55 (dd, J=17.39, 8.58 Hz, 1H) 2.62 (s,3H) 4.07 (br. s., 1H) 4.36-4.48 (m, 1H) 4.91-5.02 (m, 3H) 5.59 (dd,J=1.00 Hz, 1H) 6.67 (d, J=3.30 Hz, 1H) 7.22 (t, J=8.58 Hz, 2H) 7.45-7.56(m, 2H) 7.65 (d, J=3.30 Hz, 1H) 8.60 (s, 1H) and F-4 Isomer B (1.3 mg,1.3% two steps)

LCMS [M+1] 360.15. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.84-1.94 (m, 1H)2.09-2.16 (m, 1H) 2.64 (s, 3H) 3.83 (q, J=4.40 Hz, 1H) 4.24-4.35 (m, 1H)4.80 (d, J=4.52 Hz, 1H) 4.89-5.04 (m, 2H) 5.72-5.83 (m, 1H) 6.71 (d,J=3.55 Hz, 1H) 7.20-7.30 (m, 2H) 7.47 (dd, J=8.13, 5.81 Hz, 2H) 7.66 (d,J=3.55 Hz, 1H) 8.61 (s, 1H)

Example 23 (Scheme G):(1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol(G-7) Example 24 (Scheme G):(1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol(G-9)

Step 1: Synthesis of(3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylicacid (G-1)

A mixture of A-5 (200 mg, 0.48 mmol) and LiOH (40.6 mg, 0.966 mmol) inTHF (2 mL)/H₂O (2 mL) was stirred at rt (25° C.) for 2 hrs. The mixturewas diluted with water (5 mL) and adjusted with 1N HCl to pH=2 andextracted with EtOAc (10 mL×2). The extract was dried over Na₂SO₄ andconcentrated in vacuo to afford crude G-1 (200 mg) as yellow gum, usedin the next step directly. LCMS [M+1] 338; ¹H NMR (400 MHz, DMSO-d₆) δppm 8.65 (s, 1H), 7.97 (d, J=3.8 Hz, 1H), 6.72 (d, J=3.5 Hz, 1H),5.17-5.07 (m, 1H), 5.01-4.90 (m, 2H), 3.03-2.93 (m, 1H), 2.60-2.53 (m,2H), 1.49 (s, 3H), 1.23 (s, 3H)

Step 2: Synthesis of(3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxamide(G-2)

To a suspension of crude G-1 (200 mg, 461 mmol) andN,O-dimethylhydroxylamine-HCl (70 mg, 0.72 mmol) in THF (4 mL) was addedDIPEA (186 mg, 1.44 mmol) and 50% T3P (458 mg, 0.42 mL, 1.5 mmol) at rt(15° C.). The resulting red solution was stirred at rt (15° C.) for 20hrs. Some solid was formed in the reaction mixture. The mixture waspoured into NaHCO₃ aq (15 mL) and extracted with EtOAc (10 mL×3). Theextract was washed with brine (10 mL×2), dried over Na₂SO₄ andconcentrated in vacuo to afford G-2 (150 mg, 82% in two steps) as yellowgum. LCMS [M+1] 381; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.66 (s, 1H), 7.42(d, J=3.5 Hz, 1H), 6.67 (d, J=3.8 Hz, 1H), 5.27 (dd, J=5.1, 7.2 Hz, 1H),5.06 (dd, J=5.0, 7.0 Hz, 1H), 4.92 (dd, J=5.5, 7.0 Hz, 1H), 3.78 (s,3H), 3.64-3.51 (m, 1H), 3.25 (s, 3H), 2.70-2.42 (m, 2H), 1.61 (s, 3H),1.32 (s, 3H)

Step 3: Synthesis of(4-chloro-3-fluorophenyl)((3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanone (G-3)

To a solution of G-2 (150 mg, 0.394 mmol) in dry THF (3 mL) was added(4-chloro-3-fluorophenyl)magnesium bromide (3.1 mL, 1.54 mmol) at 0° C.The mixture was stirred at 0° C. for 3 hr. The mixture was quenched withNH₄Cl aq (20 mL) and diluted with EtOAc (10 mL×2). The organic layer waswashed with brine (10 mL), dried over Na₂SO₄ and concentrated in vacuoto afford crude G-3 (250 mg, >99%) as a yellow oil which was used in thenext step directly.

LCMS [M+1] 450

Step 4: Synthesis of(S)-(4-chloro-3-fluorophenyl)((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (G-4) and(R)-(4-chloro-3-fluorophenyl)((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(G-5)

To a solution of crude G-3 (150 mg, 0.4 mmol) in MeOH (5 mL) was addedNaBH₄ (45 mg, 1.18 mmol) at 0° C. The mixture was stirred at 0° C. for 1hr. The mixture was quenched with NH₄Cl aq (10 mL) and diluted withEtOAc (10 mL×3). The organic layer was washed with brine (10 mL), driedover Na₂SO₄ and concentrated in vacuo then purified by silica gelchromatography eluting with EtOAc in petroleum ether from 0 to 60% toafford G-4 (30 mg, 17%) and G-5 (50 mg, 28%) as a light yellow solid.

G-4: LCMS [M+1] 452

G-5: LCMS [M+1] 452

Step 5: Synthesis of(S)-((3aR,4R,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-chloro-3-fluorophenyl)methanol(G-6)

A mixture of G-4 (30 mg, 0.0663 mmol) in dioxane/NH₃.H₂O (1 mL/1 mL) washeated at 120° C. under microwave for 2 h. LCMS showed most of SM wasconsumed and a good spot was formed. The mixture was concentrated invacuo to afford crude G-6 (50 mg, >100%) as yellow solid, used in thenext step directly. LCMS [M+1] 433

Step 6: Synthesis of(1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol(G-7)

A mixture of G-6 (30 mg, 0.0663 mmol) in TFA/H₂O (1 mL/1 mL) was stirredat rt (25° C.) for 1 hr. LCMS showed most of SM was consumed and mainpeak was desired compound. The mixture was poured into 20% K₂CO₃ aq (10mL) and extracted with EtOAc (10 mL×2). The extract was washed withbrine (10 mL×2), dried over Na₂SO₄ and concentrated in vacuo to affordcrude material which was purified by prep-HPLC to afford G-7 (10 mg,37%) as a white solid. LCMS [M+1] 393; ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.01 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.35 (dd, J=1.6, 10.4 Hz, 1H),7.27-7.18 (m, 2H), 6.92 (s, 2H), 6.55 (d, J=3.5 Hz, 1H), 5.74 (d, J=5.3Hz, 1H), 4.85 (d, J=6.5 Hz, 1H), 4.84-4.73 (m, 2H), 4.62 (d, J=4.8 Hz,1H), 4.24-4.10 (m, 1H), 3.91 (q, J=4.9 Hz, 1H), 2.21 (td, J=4.3, 8.5 Hz,1H), 1.90-1.64 (m, 2H)

Compound G-9 was prepared from G-5 (10 mg, 37%) as a white solid in asimilar method as G-7 was prepared from G-4.

G-9: LCMS [M+1] 393; ¹H NMR (40 0 MHz, DMSO-d₆) δ ppm 8.02 (s, 1H), 7.54(t, J=8.0 Hz, 1H), 7.40 (dd, J=1.6, 10.7 Hz, 1H), 7.30-7.24 (m, 1H),7.21 (d, J=3.5 Hz, 1H), 6.92 (s, 2H), 6.54 (d, J=3.5 Hz, 1H), 5.76 (d,J=4.5 Hz, 1H), 4.87-4.76 (m, 2H), 4.61 (t, J=5.5 Hz, 1H), 4.51 (d, J=3.8Hz, 1H), 4.28-4.19 (m, 1H), 3.93-3.88 (m, 1H), 2.23 (d, J=8.5 Hz, 1H),2.06-1.94 (m, 1H), 1.66-1.52 (m, 1H)

Example 25 (Scheme H):(1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(H-5) Example 26 (Scheme H):(1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(H-6)

Step 1: Synthesis of(3aR,4S,6R,6aS)-6-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxamide(H-1)

To a solution of G-2 (Scheme G) (400 mg, 1.05 mmol) in 20 mL anhydrousCH₃CN was added selectfluor (558 mg, 1.58 mmol) and AcOH (10 ml). Themixture was heated at 70° C. for 6 hours in an atmosphere of N₂. Thereaction mixture was concentrated, H₂O and EtOAc were added, the aqueouswas extracted 3 times with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, concentrated to give brown oil.

The above brown oil was added 2,2-dimethoxypropane (109 mg, 1.05 mmol,3.50 mL, 0.3 M) and toluenesulfonic acid monohydrate (599 mg, 3.15mmol), the yellow brown suspension was stirred vigorously at r.t. for 15min. The reaction mixture was diluted with 50 mL H₂O, neutralized withsolid NaHCO₃, the volatiles were carefully removed in vacuo and theresulting brown aqueous solution was extracted with EtOAc 3×20 mL, theorganic was combined and concentrated, purified by column chromatographywith 60% EtOAc/heptane to give 100 mg of H-1 (24% yield) as a colorlessgum.

LCMS [M+1] 398.80. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.63 (s, 1H)7.22 (d, J=2.57 Hz, 1H) 5.25-5.36 (m, 1H) 5.01 (dd, J=7.03, 4.95 Hz, 1H)4.83 (dd, J=6.97, 5.50 Hz, 1H) 3.77 (s, 3H) 3.58 (d, J=7.34 Hz, 1H) 3.25(s, 3H) 2.58-2.68 (m, 1H) 2.38-2.52 (m, 1H) 1.61 (s, 3H) 1.31 (s, 3H)

Step 2: Synthesis of((3aR,4S,6R,6aS)-6-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanone(H-2)

Following a similar procedure to step 8 in Scheme A using4-fluorophenylmagnesium bromide and H-1 to give H-2 (100 mg, 92%).

LCMS [M+1] 433.70. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.62 (s, 1H)8.07-8.16 (m, 2H) 7.14-7.23 (m, 3H) 5.25-5.37 (m, 1H) 4.98 (dd, J=6.91,4.58 Hz, 1H) 4.86-4.93 (m, 1H) 4.03 (ddd, J=10.30, 7.79, 4.52 Hz, 1H)2.58-2.76 (m, 2H) 1.67 (s, 3H) 1.32 (s, 3H)

Step 3: Synthesis of((3aR,4R,6R,6aS)-6-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanol(H-3)

Following a similar procedure to step 4 in Scheme G, H-2 was reduced toH-3 (88 mg, 88%).

LCMS [M+1] 435.70.

Step 4: Synthesis of((3aR,4R,6R,6aS)-6-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanol(H-4)

Following a similar procedure to step 5 in Scheme G, H-3 was transformedto H-4 as crude for next step.

LCMS [M+1] 417.80.

Step 5: Synthesis of(1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(H-5) and(1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(H-6)

Following a similar procedure to step 6 in Scheme G and subsequentpurification by chiral SFC, H-4 was deprotected and the isomersseparated into H-5 and H-6 (26.5 mg, 35%).

H-5: LCMS [M+1] 376.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.01 (s, 1H)7.40 (dd, J=8.36, 5.72 Hz, 1H) 7.19 (s, 1H) 7.13 (t, J=8.80 Hz, 1H) 6.85(br. s., 1H) 5.52 (d, J=4.62 Hz, 1H) 4.87 (q, J=9.68 Hz, 1H) 4.77 (d,J=6.82 Hz, 1H) 4.53 (dd, J=7.04, 4.62 Hz, 1H) 4.51 (d, J=3.52 Hz, 1H)4.16 (dt, J=9.63, 5.97 Hz, 1H) 3.93 (br. s., 1H) 2.16-2.22 (m, 1H) 1.86(dt, J=13.04, 8.78 Hz, 1H) 1.42 (ddd, J=12.98, 10.56, 8.14 Hz, 1H)

H-6: LCMS [M+1] 376.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.01 (s, 1H)7.37 (dd, J=8.47, 5.61 Hz, 1H) 7.23 (d, J=1.76 Hz, 1H) 7.12 (t, J=8.80Hz, 1H) 6.87 (br. s., 1H) 5.51 (d, J=4.84 Hz, 1H) 4.82-4.88 (m, 1H)4.79-4.82 (m, 1H) 4.76 (t, J=4.84 Hz, 1H) 4.58 (d, J=4.62 Hz, 1H) 4.10(dt, J=8.36, 6.05 Hz, 1H) 3.80-3.86 (m, 1H) 2.17 (tt, J=8.64, 4.46 Hz,1H) 1.79 (dt, J=13.09, 8.53 Hz, 1H) 1.68 (dt, J=12.93, 9.60 Hz, 1H)

Example 27 (SchemeI)—(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol(I-12) Example 28 (SchemeI)—(1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol(I-13)

Step 1: Synthesis of tert-butyl(3aS,4R,7S,7aR)-2,2-dimethyl-6-oxotetrahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-5(4H)-carboxylate (I-2)

To a solution of(3aS,4R,7S,7aR)-2,2-dimethyltetrahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridin-6(3aH)-oneI-1 (Chemical Reviews, 2012, 112 (8), pp 4642-4686) (5000 mg, 27.29mmol) and Boc anhydride (7.15 g, 32.7 mmol) in THF (54.6 mL, c=0.5 M)was added triethylamine (3.31 g, 32.7 mmol, 4.56 mL) and DMAP (333 mg,2.73 mmol). The reaction was stirred at r.t. for 3 hrs. The mixture wasconcentrated to a tan solid which was purified by column chromatographywith 30% EtOAc/Heptane to give 7.9 g of I-2 (100% yield) as a whitesolid.

LCMS [M+1-tBu] 228. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.60 (d, J=5.4Hz, 1H), 4.49 (d, J=5.4 Hz, 1H), 4.44 (s, 1H), 2.90 (s, 1H), 2.16-2.07(m, 1H), 2.05-1.96 (m, 1H), 1.53 (s, 9H), 1.50 (s, 3H), 1.37 (s, 3H).

Step 2: Synthesis of tert-butyl((3aS,4R,6S,6aR)-6-(3,4-difluorobenzoyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate(I-3)

To a solution of I-2 (1.42 g, 5.00 mmol) in THF (10.0 mL, c=0.5 M)cooled in an ice-water bath was added 4-fluorophenylmagnesium bromide(997 mg, 5 mmol, 5.00 mL, 1 M). The reaction mixture was stirred at icebath for 10 min, quenched by adding 50 mL MeOH and 50 mL std. NH₄Clwhile cooling in ice bath. The aqueous layer was extracted with EtOAc,the organic layer was concentrated, purified by column chromatographywith 30% EtOAc/heptane to give 4.15 g of I-3 (93% yield) as a whitesolid.

LCMS [M+1-Boc] 298. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84-7.95 (m,2H) 7.29-7.35 (m, 1H) 5.43 (br. s., 1H) 4.77 (d, J=5.50 Hz, 1H) 4.51 (d,J=5.62 Hz, 1H) 4.18 (br. s., 1H) 3.87 (d, J=8.68 Hz, 1H) 2.53 (d, J=6.85Hz, 1H) 2.04 (d, J=13.94 Hz, 1H) 1.55 (s, 3H) 1.45 (s, 9H) 1.31 (s, 3H)

Step 3: Synthesis of tert-butyl((3aS,4R,6R,6aR)-6-((3,4-difluorophenyl)(hydroxy)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate(I-4)

To a solution of I-3 (4531 mg, 11.40 mmol) in EtOH (57.0 mL, c=0.2 M)was added NaBH₄ (2160 mg, 57.0 mmol), stirred at r.t. for 30 min. Thereaction was quenched by adding std. NH₄Cl, extracted with EtOAc, theorganic layers were concentrated, purified by column chromatographyeluting with 50% EtOAc/heptane to give 4120 mg of I-4 (90% yield) as awhite solid. LCMS [M+1-Boc] 300.

Step 4: Synthesis of tert-butyl((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate(I-5)

To a solution of I-4 (4300 mg, 10.77 mmol) and imidazole (2200 mg, 32.3mmol) in DMF (53.8 mL, c=0.2 M) was added t-butyldimethylsilyl chloride(4870 mg, 32.3 mmol). The mixture was stirred at r.t. overnight.Additional TBSCl (1620 mg, 10.8 mmol) was added and stirred at r.t.overnight. The reaction mixture was quenched with H₂O and extracted withEtOAc (×3). The organic layer was dried over Na₂SO₄, concentrated,purified by column chromatography with 15-20% EtOAc/heptane to give 5.27g of I-5 (87% yield) as a colorless oil which solidified upon vacuum.LCMS [M+1-Boc] 414.

Step 5: Synthesis of mixture of(3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-amine(I-6) and(1R,2S,3R,5S)-3-amino-5-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)cyclopentane-1,2-diol(I-7)

I-5 (1250 mg, 2.433 mmol) in TFA (5.0 mL, c=0.5 M) was stirred at r.t.for 10-15 min. The reaction mixture was added EtOAc and neutralized withstd. NaHCO₃ until pH about 7, the aqueous layer was extracted withEtOAc, the organic was combined and dried over Na₂SO₄, concentrated togive 1 g (99% yield) as a light yellow oil as a mixture of the twocompounds I-6 and I-7.

Step 6: Synthesis of mixture ofN-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(I-8) and(1R,2S,3R,5S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)cyclopentane-1,2-diol(I-9)

To the above compounds I-6 and I-7 (154 mg, 0.372 mmol) in 4 mL nBuOHsolution was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (85.8 mg, 0.559mmol) and DIPEA (96.3 mg, 0.745 mmol, 0.123 mL), heated at 100° C. for 2days. The reaction mixture was cooled to r.t., EtOAc was added. Theorganic layer was washed with H₂O three times and then brine, dried overNa₂SO₄, concentrated, purified by column chromatography eluting from 80%EtOAc/heptane to 10% EtOAc/MeOH to give 35.3 mg (19% yield) of a mixtureof two compounds I-8 and I-9 as a brown oil.

Step 7: Synthesis of mixture of((3aR,4R,6R,6aS)-6-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol(I-10) and(1R,2S,3R,5R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-((3,4-difluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol (I-11)

To a mixture of the above compounds I-8 and I-9 (49 mg, 0.10 mmol) in 1mL THF was added TBAF (39.2 mg, 0.150 mmol, 0.15 mL, 1.0 M) dropwise,stirred at r.t. for 0.5 h, concentrated and used crude for next step.

Step 8: Synthesis of(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol(I-12) and (1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol(I-13)

A mixture of above compounds I-10 and I-11 (42 mg, 0.10 mmol) wasdissolved in TFA/H₂O (1 mL/1 mL) and stirred at rt for 2 h. Aftercompletion, the mixture was concentrated to give crude oil, which wasdissolved in H₂O, washed with EtOAc (1 mL×2). The water layer waslyophilizated and the mixture separated by supercritical CO₂ fluidchromatography to give(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diolI-12 (5.88 mg, 15%) and(1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diolI-13 (5.72 mg, 15%).

I-12: LCMS [M+1] 376.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.06-1.12 (m,1H) 1.88-1.96 (m, 1H) 2.15-2.21 (m, 1H) 2.88 (q, J=6.83 Hz, 1H) 3.77 (t,J=6.15 Hz, 1H) 3.88 (br. s., 1H) 4.24-4.32 (m, 1H) 4.47 (d, J=5.98 Hz,1H) 6.53 (br. s., 1H) 7.06 (br. s., 1H) 7.15 (br. s., 1H) 7.25-7.36 (m,3H) 7.99 (br. s., 1H)

I-13: LCMS [M+1] 376.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.32-1.40 (m,1H) 1.81 (dt, J=12.55, 8.07 Hz, 1H) 2.10-2.20 (m, 1H) 2.88 (q, J=6.83Hz, 1H) 3.75-3.81 (m, 1H) 3.83 (br. s., 1H) 4.18-4.31 (m, 1H) 4.73 (br.s., 1H) 6.55 (br. s., 1H) 7.07 (br. s., 1H) 7.14 (br. s., 1H) 7.24-7.41(m, 3H) 8.00 (br. s., 1H)

Examples 29 and 30 were prepared in using similar chemistry in Scheme Iusing 4-chloroquinazoline-8-carbonitrile in step 6 in place of4-chloro-7H-pyrrolo[2,3-d]pyrimidine.

Example 29 Isomer A

LCMS [M + 1] 412.85. 4-({(1R;2S;3R;4R)-4-[(3;4-difluorophenyl)(hydroxy)methyl]-2;3-dihydroxycyclopentyl}amino)quinazoline- 8-carbonitrile ¹H NMR (700 MHz,DMSO-d6) δ ppm 1.40 (dt, J = 13.11, 8.82 Hz, 1 H) 1.85 (dt, J = 13.15,8.20 Hz, 1 H) 2.17 (dt, J = 8.80, 4.31 Hz, 1 H) 3.86 (q, J = 4.61 Hz, 1H) 3.88-3.95 (m, 1 H) 4.43 (t, J = 7.69 Hz, 1 H) 4.75 (t, J = 4.10 Hz, 1H) 7.09-7.16 (m, 1 H) 7.22-7.32 (m, 2 H) 7.58 (t, J = 7.86 Hz, 1 H) 8.21(d, J = 7.34 Hz, 1 H) 8.38 (d, J = 7.34 Hz, 1 H) 8.40-8.46 (m, 2 H)Example 30 Isomer B

LCMS [M + 1] 412.85. 4-({(1R;2S;3R;4R)-4-[(3;4-difluorophenyl)(hydroxy)methyl]-2;3-dihydroxycyclopentyl}amino)quinazoline- 8-carbonitrile ¹H NMR (700 MHz,DMSO-d6) δ ppm 1.13-1.18 (m, 1 H) 1.92-1.99 (m, 1 H) 2.16-2.25 (m, 1 H)3.92 (br. s., 2 H) 4.42-4.52 (m, 2 H) 7.11-7.15 (m, 1 H) 7.22-7.26 (m, 1H) 7.26-7.30 (m, 1 H) 7.55-7.60 (m, 1 H) 8.21 (dd, J = 7.34, 1.20 Hz, 1H) 8.40-8.44 (m, 2 H)

Example 31 (SchemeJ)—(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(pyrimidin-4-yl)amino]cyclopentane-1,2-diol (J-5) Example 32 (SchemeJ)—(1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(pyrimidin-4-yl)amino]cyclopentane-1,2-diol(J-5)

Step 1: Synthesis of tert-butyl((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(methyl)carbamate(J-1)

Sodium hydride (304 mg, 7.59 mmol) was added in portions to a solutionof I-5 (1300 mg, 2.531 mmol) in DMF (15 mL, 0.1 M) under an atmosphereof nitrogen, after 5 min, iodomethane (1080 mg, 7.59 mmol) was added,stirred at r.t. for 30 min. The reaction mixture was added H₂O,extracted with EtOAc, concentrated and purified by column chromatographywith 20% EtOAc/heptane to give 1290 mg of J-1 (96% yield) as a colorlessoil, LCMS [M+1-Boc] 428.1.

Step 2: Synthesis of(3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-N,2,2-trimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-amine(J-2)

J-1 (967 mg, 1.83 mmol) in TFA (5.0 mL, c=0.1 M) was stirred at r.t. for10-15 min. The reaction mixture was added EtOAc and std. NaHCO₃ toneutralize to pH about 7, extracted with EtOAc, the organic layer wasdried over Na₂SO₄, concentrated to give colorless oil.

The above oil was dissolved in acetone dimethyl acetal (10 mL, c=0.1 M),toluene-4-sulfonic acid (349 mg, 1.83 mmol) was added, stirred at r.t.for 15 min. The reaction mixture was added std NaHCO₃, extracted withEtOAc, the organic layer was washed with brine, dried over Na₂SO₄,concentrated to give 0.78 g of J-2 (99% yield) as a light yellow oil.LCMS [M+1]428.15.

Step 3: Synthesis ofN-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-methylpyrimidin-4-amine(J-3)

The mixture of J-2 (200 mg, 0.468 mmol), 4-chloropyrimidine (64.3 mg,0.561 mmol) and DIPEA (121 mg, 0.935 mmol, 0.155 mL) in n-butanol (2.0mL, c=0.2 M) was heated at 120° C. overnight. The reaction mixture wascooled to r.t., the solvent was removed. The residue was added EtOAc,washed with H₂O 3 times and then brine, dried over Na₂SO₄ andconcentrated, purified by column chromatography with 70% EtOAc/heptaneto give 64 mg of J-3 (27% yield) as a brown oil. LCMS [M+1] 506.20.

Step 4: Synthesis of(3,4-difluorophenyl)((3aR,4R,6R,6aS)-2,2-dimethyl-6-(methyl(pyrimidin-4-yl)amino)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (J-4)

Followed similar procedure as step 7 in Scheme I, J-3 was deprotected togive J-4 as crude for the next step. LCMS [M+1] 392.15.

Step 5: Synthesis of(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(pyrimidin-4-yl)amino]cyclopentane-1,2-diol (J-5) and(1S,2R,3R,5R)-3-[(R)-(3;4-difluorophenyl)(hydroxy)methyl]-5-[methyl(pyrimidin-4-yl)amino]cyclopentane-1,2-diol(J-6)

Followed similar procedure as step 8 in Scheme I, J-4 (50 mg, 0.13 mmol)was deprotected to give J-5 (19.73 mg, 44%) and J-6 (3.14 mg, 7%).

J-5: LCMS [M+1] 351.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.18-1.31 (m,1H) 1.63 (d, J=9.68 Hz, 1H) 2.08-2.19 (m, 1H) 2.90 (br. s., 3H)3.73-3.82 (m, 1H) 3.90 (dd, J=9.35, 5.17 Hz, 1H) 4.38 (br. s., 1H) 4.49(d, J=5.94 Hz, 1H) 4.63 (br. s., 1H) 5.60 (br. s., 1H) 6.57-6.69 (m, 1H)7.21 (br. s., 1H) 7.31-7.42 (m, 2H) 8.02-8.14 (m, 1H) 8.41 (br. s., 1H)

J-6: LCMS [M+1] 351.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.42 (br. s.,2H) 2.10 (br. s., 1H) 2.90 (br. s., 3H) 3.76 (br. s., 1H) 3.86-3.97 (m,1H) 4.54 (br. s., 1H) 4.65 (br. s., 1H) 4.70-4.78 (m, 1H) 5.58 (br. s.,1H) 6.63 (br. s., 1H) 7.17 (br. s., 1H) 7.28-7.40 (m, 2H) 8.09 (br. s.,1H) 8.41 (br. s., 1H)

Examples 33-36 were prepared in following similar chemistry in Scheme Jusing the chloropyrimidine listed in step 3.

Example 33 4-chloro-6- methylpyrimidine

LCMS [M + 1] 366.1 (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(6-methyl pyrimidin-4-yl)amino] cyclopentane-1,2-diol¹H NMR (700 MHz, DMSO-d6) δ ppm 1.18-1.31 (m, 1 H) 1.61 (d, J = 10.34Hz, 1 H) 2.13 (d, J = 7.04 Hz, 1 H) 2.22 (s, 3 H) 2.88 (br. s., 3 H)3.77 (br. s., 1 H) 3.84-3.94 (m, 1 H) 4.32-4.41 (m, 1 H) 4.49 (t, J =5.06 Hz, 1 H) 4.61 (br. s., 1 H) 5.61 (d, J = 4.40 Hz, 1 H) 6.49 (br.s., 1 H) 7.15-7.23 (m, 1 H) 7.32-7.43 (m, 2 H) 8.28 (s, 1 H) Example 344-chloro-6- methylpyrimidine

LCMS [M + 1] 366.1 (1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(6-methylpyrimidin-4-yl)amino] cyclopentane-1,2-diol ¹HNMR (700 MHz, DMSO-d6) δ ppm 1.40 (t, J = 9.24 Hz, 2 H) 2.09 (dt, J =8.14, 4.29 Hz, 1 H) 2.22 (s, 3 H) 2.89 (br. s., 3 H) 3.71-3.78 (m, 1 H)3.86-3.95 (m, 1 H) 4.46-4.54 (m, 1 H) 4.62 (br. s., 1 H) 4.73 (t, J =4.40 Hz, 1 H) 5.58 (d, J = 4.62 Hz, 1 H) 6.50 (br. s., 1 H) 7.16 (br.s., 1 H) 7.29-7.39 (m, 2 H) 8.28 (s, 1 H) Example 35 4-chloro-2-methylpyrimidine

LCMS [M + 1] 365.90 (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(2-methyl pyrimidin-4-yl)amino] cyclopentane-1,2-diol¹H NMR (700 MHz, DMSO-d6) δ ppm 1.17-1.32 (m, 1 H) 1.57-1.68 (m, 1 H)2.08-2.19 (m, 1 H) 2.31 (br. s., 3 H) 2.88 (br. s., 3 H) 3.77 (br. s., 1H) 3.84-3.94 (m, 1 H) 4.37 (br. s., 1 H) 4.49 (br. s., 1 H) 4.63 (br.s., 1 H) 5.61 (br. s., 1 H) 6.43 (br. s., 1 H) 7.21 (br. s., 1 H) 7.37(d, J = 8.58 Hz, 2 H) 7.99 (br. s., 1 H) Example 36 4-chloro-2-methylpyrimidine

LCMS [M + 1] 365.90 (1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(2-methylpyrimidin-4-yl)amino] cyclopentane-1,2-diol ¹HNMR (700 MHz, DMSO-d6) δ ppm 1.35-1.48 (m, 2 H) 2.10 (tt, J = 8.53, 4.24Hz, 1 H) 2.31 (s, 3 H) 2.89 (br. s., 3 H) 3.71-3.79 (m, 1 H) 3.91 (dt, J= 8.42, 6.02 Hz, 1 H) 4.52 (d, J = 3.96 Hz, 1 H) 4.65 (br. s., 1 H) 4.73(t, J = 4.51 Hz, 1 H) 5.59 (d, J = 4.62 Hz, 1 H) 6.43 (d, J = 5.06 Hz, 1H) 7.12-7.19 (m, 1 H) 7.29-7.38 (m, 2 H) 7.99 (d, J = 5.94 Hz, 1 H)

Example 37 (SchemeK)—(1R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl)amino]-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (K-4) Example 38 (SchemeK)—(1R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl)amino]-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(K-5)

Step 1: Synthesis ofN-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-N-methyl-1,3,5-triazin-2-amine(K-1)

Following a similar procedure to step 3 in Scheme J using2,4-dichloro-[1,3,5]triazine with J-2 generated K-1 (267 mg, 58%).

Step 2: Synthesis ofN2-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N2-methyl-1,3,5-triazine-2,4-diamine(K-2)

Following a similar procedure to step 5 in Scheme G, K-1 was convertedto K-2 (86 mg, 81%).

LCMS [M+1] 522.

Step 3: Synthesis of((3aR,4R,6R,6aS)-6-((4-amino-1,3,5-triazin-2-yl)(methyl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol(K-3)

Following a similar procedure to step 4 in Scheme J, K-2 was deprotectedwith TBAF to give K-3 as crude for the next step.

Step 4: Synthesis of(1R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl)amino]-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(K-4) and(1R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl)amino]-5-[(3R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(K-5)

Following a similar procedure to step 5 in Scheme J with subsequentseparation with chiral SFC, K-3 was converted to K-4 (12 mg, 20%) andK-5 (48 mg, 80%).

K-4: LCMS [M+1] 367.90. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.23 (m,1H) 1.52-1.64 (m, 1H) 2.08 (br. s., 1H) 2.96 (d, J=9.78 Hz, 3H) 3.78(br. s., 1H) 3.87 (br. s., 1H) 4.48 (d, J=5.38 Hz, 1H) 4.94 (br. s., 1H)5.55 (br. s., 1H) 6.95 (s, 1H) 7.08 (br. s, 2H) 7.21 (br. s, 1H)7.30-7.45 (m, 2H) 8.07 (br. s., 1H)

K-5: LCMS [M+1] 367.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.31-1.45 (m,2H) 2.05 (br. s., 1H) 2.93 (m, 3H) 3.72 (br. s., 1H) 3.90 (br. s., 1H)4.65-4.72 (m, 1H) 4.86 (d, J=15.03 Hz, 1H) 7.14 (br. s., 1H) 7.25-7.35(m, 2H) 7.98 (br. s., 1H) 8.30 (br. s., 2H)

Examples 39-42 were prepared in following similar chemistry in Scheme Kusing 2,4-dichloropyrimidine (Examples 39 & 40) or2,4-dichloro-6-methyl-1,3,5-triazine (Examples 41 & 42) listed in step1.

Example 39 2,4- dichloropyrimidine

LCMS [M + 1] 366.90 (1R,2S,3R,5R)-3-[(2-aminopyrimidin-4-yl)(methyl)amino]-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl] cyclopentane-1,2-diol¹H NMR (700 MHz, DMSO-d6) δ ppm 1.17-1.22 (m, 1 H) 1.53-1.60 (m, 1 H)2.06-2.11 (m, 1 H) 2.81 (br. s., 3 H) 3.75 (br. s., 1 H) 3.84-3.89 (m, 1H) 4.32 (d, J = 3.08 Hz, 1 H) 4.48 (t, J = 5.28 Hz, 1 H) 4.60 (d, J =5.94 Hz, 1 H) 5.59 (d, J = 4.62 Hz, 1 H) 5.81 (s, 2 H) 5.87 (d, J = 5.94Hz, 1 H) 7.20 (br. s., 1 H) 7.32- 7.40 (m, 2 H) 7.67 (d, J = 5.67 Hz, 1H) Example 40 2,4- dichloropyrimidine

LCMS [M + 1] 366.90 (1R,2S,3R,5R)-3-[(2-aminopyrimidin-4-yl)(methyl)amino]-5-[(R)-(3,4 difluorophenyl)(hydroxy)methyl] cyclopentane-1,2-diol¹H NMR (700 MHz, DMSO-d6) δ ppm 1.30-1.44 (m, 2 H) 2.05 (dt, J = 8.25,4.24 Hz, 1 H) 2.82 (br. s., 3 H) 3.74 (br. s., 1 H) 3.88 (br. s., 1 H)4.48 (br. s., 1 H) 4.62 (br. s., 1 H) 4.72 (br. s., 1 H) 5.57 (d, J =4.40 Hz, 1 H) 5.81 (br. s., 2 H) 5.87 (d, J = 5.06 Hz, 1 H) 7.09-7.19(m, 1 H) 7.28-7.38 (m, 2 H) 7.67 (br. s., 1 H) Example 412,4-dichloro-6- methyl-1,3,5- triazine

LCMS [M + 1] 381.90 (1R,2S,3R,5R)-3-[(4-amino-6-methyl-1,3,5-triazin-2-yl)(methyl)amino]-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm1.18 (d, J = 13.66 Hz, 1 H) 1.49-1.59 (m, 1 H) 2.12 (d, J = 14.69 Hz, 4H) 2.91 (d, J = 19.81 Hz, 3 H) 3.79 (br. s., 1 H) 3.88 (br. s., 1 H)4.46 (br. s., 1 H) 4.88 (br. s., 1 H) 7.16 (br. s., 1 H) 7.23-7.36 (m, 2H) Example 42 2,4-dichloro-6- methyl-1,3,5- triazine

LCMS [M + 1] 381.90 (1R,2S,3R,5R)-3-[(4-amino-6-methyl-1,3,5-triazin-2-yl)(methyl)amino]-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm1.31-1.45 (m, 2 H) 2.07 (d, J = 18.62 Hz, 4 H) 2.82-2.96 (m, 3 H) 3.72(br. s., 1 H) 3.87 (br. s., 1 H) 4.68 (br. s., 1 H) 4.94-4.78 (m, 1 H)6.37 (br. s., 2 H) 7.13 (br. s., 1 H) 7.22-7.34 (m, 2 H)

Example 43 (SchemeL)—(1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (L-4) Example 44 (SchemeL)—(1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(L-5)

Step 1: Synthesis ofN-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-N-methylpyrimidin-4-amine(L-1)

Following a similar procedure to step 1 in Scheme K, J-2 was treatedwith 4,6-dichloropyrimidine in n-butanol and DIPEA to give L-1 (188 mg,60%). LCMS [M+1] 540.20.

Step 2: Synthesis ofN4-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N4-methylpyrimidine-4,6-diamine(L-2)

To a solution of L-1 (188 mg, 0.348 mmol) in THF (10 mL, c=0.035 M) wasadded tris(dibenzylideneacetone)dipalladium (41.4 mg, 0.045 mmol) anddicyclohexyl(2-phenylphenyl)phosphane (33.7 mg, 0.092 mmol), capped andpurged with nitrogen, then LHMDS (153 mg, 0.905 mmol, 0.90 mL, 1.0 M)was added, heated at 75° C. for 18 h. The reaction was cooled to r.t.,diluted with water and EtOAc, the layers were separated. The organicphase was dried over Na₂SO₄, filtered and concentrated. The product waspurified by column chromatography with 80%-100% EtOAc/heptane to give180 mg of L-2 (99% yield) as a light yellow oil. LCMS [M+1] 521.30.

Step 3: Synthesis of((3aR,4R,6R,6aS)-6-((6-aminopyrimidin-4-yl)(methyl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol(L-3)

Following a similar procedure as step 3 in Scheme K, L-2 was treatedwith TBAF to give L-3 as crude for the next step. LCMS [M+1] 407.20.

Step 4: Synthesis of(1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (L-4) and(1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(L-5)

Following a similar procedure as step 4 in Scheme K, L-3 was treatedwith TFA in water. L-4 (31 mg, 25%) and L-5 (11 mg, 9%) were isolatedafter workup and purification by chiral SFC.

L-4: LCMS [M+1] 366.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.13-1.26 (m,1H) 1.55 (dt, J=12.60, 8.56 Hz, 1H) 2.04-2.13 (m, 1H) 2.77 (s, 2H)3.71-3.79 (m, 1H) 3.81-3.88 (m, 1H) 4.27-4.35 (m, 1H) 4.47 (t, J=5.28Hz, 1H) 4.55 (d, J=5.72 Hz, 1H) 5.47 (s, 1H) 5.58 (d, J=4.62 Hz, 1H)6.03 (br. s., 2H) 7.15-7.23 (m, 1H) 7.30-7.40 (m, 2H) 7.86 (s, 1H)

L-5: LCMS [M+1] 366.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.29-1.42 (m,2H) 1.99-2.09 (m, 1H) 2.78 (br. s., 3H) 3.74 (br. s., 1H) 3.86 (d,J=7.04 Hz, 1H) 4.41-4.49 (m, 1H) 4.52-4.60 (m, 1H) 4.72 (br. s., 1H)5.47 (s, 1H) 5.56 (d, J=3.96 Hz, 1H) 6.03 (br. s., 1H) 7.15 (br. s., 1H)7.28-7.38 (m, 2H) 7.86 (s, 1H)

Example 46 (SchemeM)—(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(4-methyl-1,3,5-triazin-2-yl)amino]cyclopentane-1,2-diol(M-4) Example 47 (SchemeM)—(1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl(4-methyl-1,3,5-triazin-2-yl)amino]cyclopentane-1,2-diol(M-5)

Step 1: Synthesis ofN-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-N-methyl-1,3,5-triazin-2-amine(M-1)

The reaction mixture of J-2 (360 mg, 0.842 mmol), 2,4-dichloro-[1,3,5]triazine (152 mg, 1.01 mmol) and DIPEA (218 mg, 1.68 mmol, 0.279 mL) inDMA (5 mL, 0.16 M) was stirred at r.t. for 5 hrs. The r×n mixture wasadded EtOAc, washed with H₂O 3 times and then brine. The organic layerwas dried over Na₂SO₄ and concentrated, purified by columnchromatography with 20% EtOAc/heptane to give 267 mg of M-1 (58.6%yield) as a colorless oil. LCMS [M+1] 541.

Step 2: Synthesis ofN-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N,4-dimethyl-1,3,5-triazin-2-amine(M-2)

M-2 (176 mg, 99%) was made from M-1 following a similar procedure tostep 5 in Scheme A. LCMS [M+1] 521.

Step 3: Synthesis of(3,4-difluorophenyl)((3aR,4R,6R,6aS)-2,2-dimethyl-6-(methyl(4-methyl-1,3,5-triazin-2-yl)amino)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(M-3)

Following a similar procedure as step 3 in Scheme K, M-2 was treatedwith TBAF to give M-3 as crude for the next step. LCMS [M+1] 407.

Step 4: Synthesis of(1S,2R,3R,5R)-3-((S)-(3,4-difluorophenyl)(hydroxy)methyl)-5-(methyl(4-methyl-1,3,5-triazin-2-yl)amino)cyclopentane-1,2-diol(M-4) and (1S,2R,3R,5R)-3-((R)-(3,4-difluorophenyl)(hydroxy)methyl)-5-(methyl(4-methyl-1,3,5-triazin-2-yl)amino)cyclopentane-1,2-diol(M-5)

Following a similar procedure as step 4 in Scheme K, M-3 was treatedwith TFA in water. M-4 (78.97 mg, 64%) and M-5 (24.48 mg, 20%) wereisolated after subsequent workup and purification by chiral SFC.

M-4: LCMS [M+1] 366.90. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.34 (m,1H) 1.56-1.69 (m, 1H) 2.13 (br. s., 1H) 2.24-2.32 (m, 3H) 3.00 (s, 3H)3.78 (br. s., 1H) 3.91 (br. s., 1H) 4.33 (d, J=15.89 Hz, 1H) 4.48 (br.s., 1H) 4.60 (br. s., 1H) 4.92-5.04 (m, 1H) 5.56 (d, J=4.40 Hz, 1H) 7.22(d, J=4.52 Hz, 1H) 7.30-7.43 (m, 2H) 8.39 (d, J=14.67 Hz, 1H)

M-5: LCMS [M+1] 366.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.36-1.48 (m,2H) 2.09 (br. s., 1H) 2.27 (d, J=23.74 Hz, 3H) 2.98 (d, J=4.10 Hz, 3H)3.73 (br. s., 1H) 3.90 (m, 1H) 4.70 (br. s., 1H) 4.93 (t, J=9.99 Hz, 1H)7.15 (br. s., 1H) 7.31 (d, J=9.39 Hz, 2H) 8.34 (d, J=33.65 Hz, 1H)

Example 48 (SchemeN)—(1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(N-5) Example 49 (SchemeN)—(1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(N-6)

Step 1: Synthesis of((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol (N-1)

I-5 (616 mg, 1.54 mmol) in TFA (3 mL, c=0.5 M) was stirred at r.t. for10-15 min. The reaction mixture was added EtOAc and neutralized withstd. NaHCO₃ to pH about 7, the aqueous layer was extracted with EtOAc 3times, the organic was dried over Na₂SO₄, concentrated to give 460 mg ofN-1 (100% yield) as a white solid, used for next step. LCMS [M+1]300.15.

Step 2: Synthesis of((3aR,4R,6R,6aS)-6-((2-amino-6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol(N-2)

The mixture of N-1 (214 mg, 0.714 mmol),4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidin-2-amine (200 mg, 0.714mmol), and triethylamine (289 mg, 2.86 mmol) in 10 mL nBuOH was heatedat 135° C. in a sealed tube for 40 hrs. The reaction mixture was cooledto r.t., concentrated, H₂O was added, extracted with EtOAc, the productwas purified by column chromatography with 50-60% EtOAc/heptane to give200 mg of N-2 (51% yield) as a yellow solid. LCMS [M+1] 543.20.

Step 3: Synthesis of((3aR,4R,6R,6aS)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol(N-3)

N-2 (200 mg, 0.368 mmol) was added to acetic acid (15 mL, c=0.025 M),the solution was heated at 100° C. for 1 h. The volatiles were removedin vacuo, the residue was added EtOAc, neutralized with std. NaHCO₃, thelayers were separated and the aqueous was extracted with EtOAc 3 times.The organic layer was concentrated, purified by column chromatographywith 50% EtOAc/heptane to give 100 mg of N-3 (60% yield) as an off whitesolid. LCMS [M+1]451.10.

Step 4: Synthesis of((3aR,4R,6R,6aS)-6-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol(N-4)

Following a similar procedure to step 5 in Scheme A, N-3 was convertedto N-4 (69 mg, 85%).

LCMS [M+1] 431.15.

Step 5: Synthesis of(1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(N-5) and(1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol(N-6)

Following a similar procedure as step 4 in Scheme K, N-4 was treatedwith TFA in water. N-5 (14.6 mg, 23%) and N-6 (6.6 mg, 11%) wereisolated after subsequent workup and purification by chiral SFC.

N-5: LCMS [M+1] 390.85. ¹H NMR (700 MHz, DMSO-d6) δ ppm 7.35-7.40 (m,1H) 7.29-7.35 (m, 1H) 7.21 (br. s., 1H) 7.07 (d, J=3.74 Hz, 1H) 6.38 (d,J=3.52 Hz, 1H) 5.90 (s, 2H) 5.74 (d, J=4.40 Hz, 1H) 4.83 (d, J=6.60 Hz,1H) 4.71-4.79 (m, 1H) 4.51-4.58 (m, 2H) 4.15-4.21 (m, 1H) 3.90 (br. s.,1H) 2.38 (s, 3H) 2.18 (d, J=7.92 Hz, 1H) 1.83-1.93 (m, 1H) 1.44 (d,J=10.34 Hz, 1H)

N-6: LCMS [M+1] 390.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 7.29-7.36 (m,2H) 7.16 (br. s., 1H) 7.12 (d, J=3.52 Hz, 1H) 6.40 (d, J=3.30 Hz, 1H)5.89 (s, 2H) 5.76 (br. s., 1H) 4.86 (d, J=5.94 Hz, 1H) 4.76 (t, J=4.62Hz, 1H) 4.73 (q, J=8.88 Hz, 1H) 4.68 (br. s., 1H) 4.08-4.12 (m, 1H)3.83-3.86 (m, 1H) 2.39 (s, 3H) 2.16 (dt, J=8.53, 4.21 Hz, 1H) 1.76 (dt,J=12.98, 8.47 Hz, 1H) 1.57-1.64 (m, 1H)

Example 50 (SchemeO)—(1S,2R,3S,5R)-3-[2-amino-1-fluoro-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(O-5) Example 51 (SchemeO)—(1S,2R,3R,5R)-3-[(1S)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(O-6) Example 52 (SchemeO)—(1S,2R,3R,5R)-3-[(1R)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(O-7)

Step 1: Synthesis of2-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-fluoro-2-(4-fluorophenyl)acetonitrile(O-1)

To a mixture of E-1 (175 mg, 0.443 mmol) and zinc(II) iodide (2.12 mg,0.00664 mmol) in a sealable tube was added anhydrous 2 mL CH₂Cl₂,followed by trimethylsilyl cyanide (0.25 mL) under nitrogen. Thereaction was sealed and heated at 50° C. for 2 days. The resultingmixture was cooled in an ice bath, DAST (78.5 mg, 0.487 mmol) was addeddropwise, stirred at r.t. for 15 min. The reaction mixture was washedwith H₂O, 0.5 N HCl, std. NaHCO₃, brine and concentrated. The productwas purified by column chromatography with 50% EtOAc/heptane to give 80mg of 0-1 (43% yield) as a yellow oil. LCMS [M+1] 425.10.

Step 2: Synthesis of2-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-fluoro-2-(4-fluorophenyl)ethan-1-amine(O-2) and 2-((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-(4-fluorophenyl)ethan-1-amine(O-3)

O-1 (70 mg, 0.16 mmol) was dissolved in 0.5 mL MeOH. Cobalt (II)chloride hexahydrate (118 mg, 0.495 mmol) was added and the mixture wascooled in an ice bath. NaBH₄ (32.8 mg, 0.825 mmol) was added and thereaction stirred at 0° C. for 0.5 h. The reaction mixture was quenchedby std. NH₄Cl, extracted with EtOAc, the organic layer was washed withbrine, concentrated, purified by prep TLC plate with 5% MeOH/CH₂Cl₂ togive 20 mg of 0-2 (28% yield) as a yellow oil, (LCMS [M+1] 429.10) and22 mg of 0-3 (32% yield) as a yellow oil. (LCMS [M+1] 411.20)

Step 3: Synthesis of(1S,2R,3S,5R)-3-[2-amino-1-fluoro-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(O-4)

Following a similar procedure as step 4 in Scheme K, 0-2 was treatedwith TFA in water. 0-4 (1.2 mg, 6.6%) was isolated after subsequentworkup and purification by SFC.

LCMS [M+1] 388.90. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.62-1.73 (m, 1H)1.81 (s, 3H) 2.54-2.73 (m, 4H) 4.17 (br. s., 1H) 4.76-4.94 (m, 2H) 6.59(d, J=3.42 Hz, 1H) 7.04 (t, J=8.68 Hz, 2H) 7.29-7.42 (m, 3H) 8.46 (s,1H)

Step 4: Synthesis of(1S,2R,3R,5R)-3-[(1S)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(O-5) and(1S,2R,3R,5R)-3-[(1R)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(O-6)

Following a similar procedure as step 4 in Scheme K, 0-3 was treatedwith TFA in water. 0-5 (5.4 mg, 27%) and 0-6 (3.7 mg, 19%) were isolatedafter subsequent workup and purification by chiral SFC.

O-5: LCMS [M+1] 370.90. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.42-1.57(m, 1H) 1.65-1.79 (m, 1H) 2.24 (br. s., 1H) 2.49-2.68 (m, 3H) 2.83 (br.s., 1H) 2.96-3.10 (m, 1H) 3.31 (d, J=13.20 Hz, 1H) 4.02 (t, J=5.81 Hz,1H) 4.27 (t, J=6.79 Hz, 1H) 4.75 (br. s., 1H) 6.56 (d, J=3.18 Hz, 1H)6.98 (t, J=8.38 Hz, 2H) 7.13-7.28 (m, 2H) 7.31 (d, J=2.93 Hz, 1H) 8.45(s, 1H)

O-6: LCMS [M+1] 370.90. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.78 (d,J=9.29 Hz, 1H) 2.26-2.40 (m, 2H) 2.53-2.67 (m, 4H) 2.91-3.00 (m, 1H)3.24-3.25 (m, 1H) 3.67-3.78 (m, 1H) 4.19-4.32 (m, 1H) 4.82-4.89 (m, 1H)6.60 (d, J=3.67 Hz, 1H) 7.08 (t, J=8.68 Hz, 2H) 7.27-7.40 (m, 3H)8.44-8.52 (m, 1H)

Example 53 (SchemeP)—(1S,2R,3R,5R)-3-((S)-(2-(aminomethyl)-4-chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (P-8) Example 54 (SchemeP)—(1S,2R,3R,5R)-3-((R)-(2-(aminomethyl)-4-chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (P-9)

Step 1: Synthesis of(1R,2S,3R,5R)-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol(P-1)

(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol (4160 mg,22.6 mmol) and 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (J. Med.Chem. 10, 665, 1967) (5000 mg, 18.86 mmol) in 40 mL absolute ethanol ina sealed flask was treated with Et₃N (7630 mg, 75.4 mmol), heated at 80°C. for 18 hrs. The reaction mixture was cooled in an ice bath, the solidwas filtered and the mother liquor was concentrated to give P-1 as abrown slurry which was used directly for next step. LCMS [M+1] 375.80.

Step 2: Synthesis of(1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (P-2)

The suspension of P-1 (7088 mg, 18.86 mmol) in 30 mL dioxane, wastreated with 10 mL 1 N HCl, heated at 80° C. for 30 min. The reactionmixture was neutralized with NH₄OH to pH 7 and the volatiles wereremoved in vacuo to afford P-2 as a brown slurry which was used directlyfor next step. LCMS [M+1] 283.85.

Step 3: Synthesis of((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(P-3)

P-2 (5350 mg, 18.86 mmol) and 2,2-dimethoxypropane (50 mL, c=0.38 M) wastreated with p-toluenesulphonic acid monohydrate (7170 mg, 37.7 mmol)and the yellow brown suspension was adjusted to pH 4-5, stirredvigorously at r.t. for 15 min. The reaction mixture was diluted with 100mL H₂O, neutralized with solid NaHCO₃. The volatiles were carefullyremoved in vacuo and the resulting brown aqueous solution was extractedwith 20% isopropanol/DCM, the organic was combined, concentrated,purified by column chromatography with 50% EtOAc/DCM to 100% EtOAc togive 4.4 g of P-3 as a yellow gum (72% overall yield).

LCMS [M+1] 324.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.63 (s, 1H)7.33 (d, J=3.55 Hz, 1H) 6.63 (d, J=3.67 Hz, 1H) 4.94-5.06 (m, 2H) 4.72(dd, J=6.66, 4.46 Hz, 1H) 3.85-3.92 (m, 1H) 3.78-3.85 (m, 1H) 2.43-2.56(m, 2H) 2.28-2.42 (m, 1H) 2.09 (br. s., 1H) 1.55-1.64 (m, 3H) 1.33 (s,3H)

Step 4: Synthesis of((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(P-4)

Following a similar procedure to step 5 in Scheme A, P-3 was convertedto P-4 (930 mg, 88%).

LCMS [M+1] 304.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (s, 3H)1.53 (s, 3H) 2.21-2.34 (m, 2H) 2.38-2.47 (m, 2H) 2.75 (s, 3H) 3.75 (br.s., 1H) 3.80 (br. s., 1H) 4.65 (dd, J=6.66, 4.10 Hz, 1H) 4.86-5.00 (m,2H) 6.57 (br. s., 1H) 7.25 (br. s., 1H) 8.71 (s, 1H)

Step 5: Synthesis of(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carbaldehyde(P-5)

EDC.HCl (3110 mg, 16.2 mmol) was added to a solution of P-4 (1230 mg,4.055 mmol) in anhydrous dimethyl sulfoxide (22.5 mL, c=0.18 M).Pyridine (641 mg, 8.11 mmol) was added followed by TFA (462 mg, 4.05mmol), stirred at r.t. for 1.5 h. The reaction mixture was diluted withH₂O, extracted with EtOAc twice, the combined organic was washed withH₂O 3 times, brine, dried over Na₂SO₄, filtered and concentrated to giveP-5 (950 mg) as a brown oil (78% yield).

LCMS [M+1] 302.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 3H)1.53 (s, 3H) 2.47-2.57 (m, 1H) 2.58-2.69 (m, 1H) 2.85 (s, 3H) 3.13 (td,J=8.68, 4.28 Hz, 1H) 4.94 (dd, J=6.60, 4.16 Hz, 1H) 5.04 (td, J=8.04,4.34 Hz, 1H) 5.14 (dd, J=6.42, 4.22 Hz, 1H) 6.66 (d, J=3.42 Hz, 1H) 7.26(br. s., 1H) 8.73 (s, 1H) 9.80 (s, 1H)

Step 6: Synthesis of5-chloro-2-(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(hydroxy)methyl)benzonitrile(P-6)

To a solution of 5-chloro-2-iodobenzonitrile (1570 mg, 5.97 mmol) in dryTHF (29.9 mL, c=0.2 M) at −78° C. was added isopropylmagnesium chloride(1080 mg, 7.47 mmol, 5.74 mL, 1.3 M). The resulting solution was stirredat −78° C. for 15 min, P-5 (900 mg, 2.99 mmol) in THF (5.0 mL) was addeddropwise. The reaction mixture was transferred to an ice bath, allowedto warm up to r.t. and stirred overnight. The reaction was then quenchedwith std. NH₄Cl, extracted with EtOAc 3 times; the organic layers werecombined, washed with brine, dried over Na₂SO₄, concentrated andpurified by column chromatography with 5% MeOH/DCM to give P-6 (700 mg)as a yellow oil. LCMS [M+1] 439.10.

Step 7: Synthesis of(2-(aminomethyl)-4-chlorophenyl)((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol(P-7)

To a solution of P-6 (200 mg, 0.456 mmol) in MeOH (5 mL, c=0.09 M) wasadded cobalt(II) chloride hexahydrate (545 mg, 2.28 mmol), and NaBH₄(181 mg, 4.56 mmol). The reaction mixture was stirred at r.t. for 0.5 h,then quenched with std. NH₄Cl. The aqueous was saturated with solid NaCland extracted with 20% isopropyl alcohol/DCM multiple times. The organiclayers were concentrated and purified by preparative HPLC to give 50 mgof P-7 as a colorless oil (13% two steps). LCMS [M+1] 443.10.

Step 8: Synthesis of(1S,2R,3R,5R)-3-((S)-(2-(aminomethyl)-4-chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (P-8) and(1S,2R,3R,5R)-3-((R)-(2-(aminomethyl)-4-chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(P-9)

Following a similar procedure as step 4 in Scheme K, P-7 was treatedwith TFA in water. P-8 (5.5 mg, 12% yield) and P-9 (0.2 mg, 0.4% yield)were isolated after subsequent workup and purification by chiral SFC.LCMS [M+1] 403.00.

Example 55 (SchemeQ)—(1S,2R,3S,5R)-3-(2-(aminomethyl)-4-chlorobenzyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (Q-4)

Step 1: Synthesis of7-((3aS,4R,6S,6aR)-6-(iodomethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine(Q-1)

The solution of triphenylphosphine (529 mg, 1.98 mmol) and imidazole(135 mg, 1.98 mmol) in methylene chloride (8.24 mL, c=0.2 M) was addedI₂ (502 mg, 1.98 mmol) followed by dropwise addition of P-4 (500 mg,1.65 mmol) in 2 mL methylene chloride. The resulting reaction mixturewas stirred at r.t. overnight, and then diluted with water (20 mL),extracted with methylene chloride (3×20 mL). The combined organic layerswere dried over Na₂SO₄, concentrated and purified by columnchromatography with 60% EtOAc/heptane to give 280 mg of Q-1 as a yellowoil (25% yield).

LCMS [M+1] 414.00. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3H)1.60 (s, 3H) 2.26-2.37 (m, 1H) 2.40 (dd, J=11.55, 5.93 Hz, 1H) 2.59 (dt,J=12.29, 6.08 Hz, 1H) 2.80 (s, 3H) 3.41 (dd, J=10.03, 6.72 Hz, 1H) 3.50(dd, J=10.09, 4.83 Hz, 1H) 4.56 (t, J=6.11 Hz, 1H) 5.02-5.13 (m, 2H)6.64 (d, J=3.55 Hz, 1H) 7.28 (d, J=3.55 Hz, 1H) 8.79 (s, 1H)

Step 2: Synthesis of5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)benzonitrile(Q-2)

To a suspension of zinc (318 mg, 4.87 mmol) in dry degassed DMF (8.11mL, c=0.1 M) was added 1,2-dibromoethane (33 mg, 0.17 mmol, 15 uL) undernitrogen. The mixture was heated with a heat gun for about 30 sec untilthe gas started to evolve from the solution indicating the activation ofzinc. The mixture was allowed to cool to r.t. TMSCl (19 mg, 0.18 mmol,23 uL) was added and the reaction was stirred at r.t. for 15 minfollowed by the addition of a solution of Q-1 (335 mg, 0.811 mmol) indry degassed DMF (1 mL). The resulting mixture was heated at 60° C. for5 min, then stirred at r.t. for 30 min. After allowing the zinc solidsto settle, the reaction mixture was filtered through a syringe filterinto a mixture of 5-chloro-2-iodobenzonitrile (214 mg, 0.812 mmol),Pd₂(dba)₃ (37.2 mg, 0.0406 mmol) and tri-o-tolylphosphine (49.4 mg,0.162 mmol) in 1 mL dry degassed DMF. The reaction mixture was flushedwith nitrogen, and stirred at 80° C. for 2 h. After cooling to r.t., thereaction mixture was partitioned between H₂O (30 mL) and EtOAc (30 mL).The organic phase was separated, washed with H₂O (3×30 mL) and brine(1×30 mL), dried over Na₂SO₄, concentrated and purified by columnchromatography with 70% EtOAc/heptane to give 25 mg of Q-2 (7.3% yield).

LCMS [M+1] 423.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 3H)1.56 (s, 3H) 2.21-2.38 (m, 2H) 2.48-2.60 (m, 1H) 2.78 (s, 3H) 2.95-3.04(m, 1H) 3.24 (dd, J=14.18, 6.72 Hz, 1H) 4.62 (t, J=6.72 Hz, 1H)4.92-5.01 (m, 1H) 5.04 (dd, J=7.09, 5.38 Hz, 1H) 6.61 (d, J=3.67 Hz, 1H)7.25 (d, J=3.67 Hz, 1H) 7.36 (d, J=8.31 Hz, 1H) 7.52 (dd, J=8.44, 2.20Hz, 1H) 7.60 (d, J=2.20 Hz, 1H) 8.76 (s, 1H)

Step 3: Synthesis of(5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)phenyl)methanamine(Q-3)

Following a similar procedure as step 7 in Scheme P, Q-2 was reduced toQ-3 as crude for the next step. LCMS [M+1] 427.10.

Step 4: Synthesis of(1S,2R,3S,5R)-3-(2-(aminomethyl)-4-chlorobenzyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (Q-4)

Following a similar procedure as step 4 in Scheme K, Q-3 was treatedwith TFA in water. Q-4 (9.5 mg, 35%) was isolated after subsequentworkup and purification by chiral SFC.

Q-4: LCMS [M+1] 386.85. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.48-1.56 (m,1H) 1.97-2.04 (m, 1H) 2.11 (br. s., 1H) 2.53-2.60 (m, 5H) 2.91 (dd,J=14.09, 5.72 Hz, 1H) 3.68-3.78 (m, 2H) 4.29 (t, J=6.23 Hz, 1H) 4.84 (q,J=8.37 Hz, 1H) 6.63 (d, J=3.42 Hz, 1H) 7.09-7.17 (m, 2H) 7.41 (br. s.,1H) 7.62 (d, J=2.22 Hz, 1H) 8.53 (s, 1H)

Example 56 (SchemeR)—(1S,2R,3R,5R)-3-((S)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(R-7) Example 57 (SchemeR)—(1S,2R,3R,5R)-3-((R)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(R-8) Scheme R

Step 1: Synthesis of tert-butyl8-iodo-3,4-dihydroisoquinoline-2(1H)-carboxylate (R-2)

A mixture of tert-butyl8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (R-1) (1100 mg, 3.52mmol), NaI (4.76 g, 31.8 mmol), CuI (402 mg, 2.12 mmol) andtrans-N,N-dimethylcyclohexane (602 mg, 4.22 mmol) in dioxane (20 mL) waspurged with N₂ for 10 min. The resulting yellow suspension was stirredat 110° C. in a sealed tube for 48 hrs. The reaction was diluted withpetroleum ether (50 mL) and filtered. The filtrate was concentrated invacuo and residue was purified by silica gel chromatography eluted withEtOAC in petroleum ether from 0 to 20% to afford R-2 (1200 mg, 94.8%) asa light yellow gum. LCMS [M+1-tBu] 304; ¹H NMR (400 MHz, CDCl₃) δ ppm7.70 (d, J=7.8 Hz, 1H), 7.45-7.39 (m, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.88(s, 1H), 4.44 (br. s., 2H), 3.62 (t, J=5.5 Hz, 2H), 2.81 (d, J=4.8 Hz,2H), 1.50 (s, 9H)

Step 2: Synthesis of(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)boronic acid(R-3)

To a solution of R-2 (250 mg, 0.696 mmol) and triisopropyl borate (262mg, 0.321 mmol) in dry THF (8 mL) was added 2.5 M n-BuLi (0.418 mL, 1.04mmol) at −60° C. the mixture was stirred at −60° C. for 30 min. Themixture was poured into NH₄Cl aq (15 mL) and extracted with EtOAc (10mL×3). The extract was dried over Na₂SO₄ and concentrated in vacuo toafford crude. The crude was purified by silica gel chromatography elutedwith MeOH in DCM from 0 to 10% to afford R-3 (180 mg, 93%) as a lightyellow gum which was used in the next step directly.

Step 3: Synthesis of S-(p-tolyl)(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carbothioate(R-4)

To compound A-7 (270 mg, 0.851 mmol) in THF was added4-methylbenzenethiol (211 mg, 1.7 mmol), DIPEA (440 mg, 3.4 mmol) andT3P (1.08 g, 1.7 mmol) at rt (15° C.). The mixture was stirred at rt5-10° C. for 2 days. The mixture was poured into NaHCO₃ aq (20 mL) andextracted with EtOAc (10 mL×2). The extract was washed with brine (15mL) and concentrated in vacuo, then purified by silica gelchromatography eluted with EtOAc in petroleum ether from 0 to 100% toafford R-4 (320 mg, 89%) as a white solid. LCMS [M+1] 424

Step 4: Synthesis of tert-butyl8-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(R-5)

A mixture of R-4 (125 mg, 0.3 mmol) and R-3 (180 mg, 0.32 mmol), CuTC(90 mg, 0.47 mmol), Pd₂(dba)₃.CHCl₃ (31 mg, 0.03 mmol) and TFP (20.6 mg,0.0886 mmol) in dry THF (5 mL) was degassed with N₂ four times. Themixture was stirred at 50° C. in a sealed tube for 16 hours. The mixturewas diluted with EtOAc (10 mL) and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography eluted with EtOAc in petroleum ether from 0 to 100% toafford R-5 (70 mg, 40%) as a white solid. LCMS [M+1] 533

Step 5: Synthesis of tert-butyl8-(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(hydroxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(R-6)

To a solution of R-5 (70 mg, 0.131 mmol) in MeOH (2 mL) was added NaBH₄(86.9 mg, 2.30 mmol) at rt 15° C. The mixture was stirred at rt 15° C.for 30 min. The mixture was diluted with water (10 mL) and extractedwith EtOAc (10 mL×3). The extract was washed with brine (10 mL), driedover Na₂SO₄ and concentrated in vacuo to afford crude R-6 (60 mg, 85%)as a light yellow solid.

Step 6: Synthesis of(1S,2R,3R,5R)-3-((S)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(R-7) and(1S,2R,3R,5R)-3-((R)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(R-8)

To compound R-6 (60 mg, 0.1 mmol) was added TFA/H₂O (1 mL/1 mL, cooledto 0° C. previously). The mixture was stirred at rt (15° C.) for 3 hrs.The mixture was concentrated in vacuo to afford crude which was purifiedby SFC. After SFC, the products were re-purified by prep TLC to obtainR-7 (4.5 mg, 13%) and R-8 (3.5 mg, 9%) as white solids.

R-7: LCMS [M+1] 395; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.59(d, J=3.8 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.06(d, J=7.3 Hz, 1H), 6.73 (d, J=3.8 Hz, 1H), 5.09-5.01 (m, 1H), 4.81 (d,J=7.0 Hz, 1H), 4.64 (dd, J=5.3, 9.5 Hz, 1H), 4.31 (dd, J=2.0, 5.5 Hz,1H), 4.29-4.16 (m, 2H), 3.21-3.06 (m, 2H), 2.92 (d, J=4.0 Hz, 2H), 2.72(s, 3H), 2.56-2.47 (m, 1H), 2.22 (td, J=8.8, 13.1 Hz, 1H), 1.83 (ddd,J=8.3, 10.7, 13.1 Hz, 1H)

R-8: LCMS [M+1] 395; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.72(d, J=3.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.23-7.17 (m, 1H), 7.07 (d,J=7.5 Hz, 1H), 6.77 (d, J=3.8 Hz, 1H), 5.12-5.04 (m, 2H), 4.48-4.42 (m,1H), 4.30-4.15 (m, 2H), 4.14-4.10 (m, 1H), 3.24-3.18 (m, 2H), 3.00-2.94(m, 2H), 2.74 (s, 3H), 2.45-2.36 (m, 1H), 2.20-2.14 (m, 1H) 2.09-1.99(m, 1H)

Example 58 (SchemeS)—(1S,2R,3S,5R)-3-(4-fluorobenzyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(S-1)

A mixture of(1S,2R,3R,5R)-3-((R)-(4-fluorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(Example 10) (30 mg, 0.084 mmol), trifluoroacetic acid (302 ul) andtriethylsilane (268 ul, 1.68 mmol) was heated to 50° C. for 2 hours. Thereaction mixture was concentrate to an oil then lithiumhydroxidemonohydrate (20 mg, 0.48 mmol) and methanol (1 ml) were added andstirred at r.t. for 45 min. The reaction mixture was concentrated toremove methanol then partitioned between water and EtOAc. The EtOAclayer was washed with brine, dried with Na₂SO₄, filtered andconcentrated to give S-1 as an oil in 52% yield.

LCMS-APCI(+): MH+=342, ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.58 (s, 1H),7.64 (d, J=3.5 Hz, 1H), 7.25 (dd, J=5.9, 8.1 Hz, 2H), 7.08 (t, J=8.8 Hz,2H), 6.68 (d, J=3.5 Hz, 1H), 4.98-4.84 (m, 2H), 4.77 (d, J=4.4 Hz, 1H),4.44-4.23 (m, 1H), 3.82-3.75 (m, 1H), 2.92 (dd, J=6.6, 13.6 Hz, 1H),2.68-2.57 (m, 4H), 2.26-2.12 (m, 1H), 2.06 (td, J=8.3, 13.0 Hz, 1H),1.60-1.41 (m, 1H)

Example 59 (SchemeT)—(+/−)-(1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-5) Example 60 (SchemeT)—(1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-6) Example 61 (SchemeT)—(1R,2R,3R,5S)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-7)

Step 1:(+/−)-(3aR,4S,6R,6aS)-6-((5-bromo-6-methylpyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol.(T-2)

A mixture of(+/−)-(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (T-1) (786 mg, 4.54 mmol),5-bromo-4-chloro-6-methylpyrimidine (1.04 g, 4.99 mmol) andtrimethylamine (0.822 ml, 5.9 mmol) in ethanol (9.0 ml, 0.5 M) washeated to 80° C. for 20 hours. The crude reaction mixture wasconcentrated to a solid then purified by silica gel chromatography witha gradient of 0% to 100% EtOAc in heptane to give T-2 as white solid,1.35 g (87% yield).

LCMS-ESI(+): MH+=344/346, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.29 (s,1H), 4.60 (d, J=6.4 Hz, 1H), 4.56-4.52 (m, 1H), 4.51-4.47 (m, 1H), 4.22(d, J=3.9 Hz, 1H), 2.33-2.23 (m, 1H), 1.76 (d, J=14.2 Hz, 1H), 1.41 (s,3H), 1.27 (s, 3H).

Step 2: Synthesis of(+/−)-(3aR,4S,6R,6aS)-6-((5-((E)-2-ethoxyvinyl)-6-methylpyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol.(T-3)

To a solution of T-2 (2.06 g, 5.98 mmol) and(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g,5.98 mmol) in dioxane (19.9 ml, 0.3 M) was vacuum flushed with nitrogenthen 2N sodium carbonate (aq) (8.98 ml) was added followed by S-Phospre-catalyst (136 mg, 0.180 mmol). The resulting mixture was heated to80° C. for 23 hours. The reaction mixture was cooled to r.t. thendiluted with EtOAc and water. The organic layer was washed with brine,dried with Na₂SO₄, filtered and concentrated to an oil then purified bysilica gel chromatography eluting with a gradient of 0% to 100% EtOAc inheptane to give T-3 as a white solid, 1.21 g (60% yield).

LCMS-ESI(+): MH+=336, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1H), 6.66(d, J=13.2 Hz, 1H), 6.38 (d, J=8.6 Hz, 1H), 5.63 (d, J=2.4 Hz, 1H), 5.32(d, J=13.2 Hz, 1H), 4.50-4.33 (m, 3H), 4.07 (br. s., 1H), 3.87 (q, J=6.9Hz, 2H), 2.24 (s, 3H), 2.12 (td, J=5.2, 13.6 Hz, 1H), 1.62 (d, J=13.9Hz, 1H), 1.34 (s, 3H), 1.25 (t, J=7.0 Hz, 3H), 1.18 (s, 3H)

Step 3: Synthesis of(+/−)-7-((3aS,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. (T-4)

A mixture of(+/−)-(3aR,4S,6R,6aS)-6-((5-((E)-2-ethoxyvinyl)-6-methylpyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol(111 mg, 0.331 mmol) and trifluoroacetic acid (127 ul, 1.65 mmol) inacetone (3.31 ml, 0.1 M) was heated to 60° C. for 43 hours. The reactionmixture was concentrated to an oil then azeotroped with toluene. Thecrude oil was dissolved in acetone (3.31 ml) then DMP (81 ul, 0.662mmol) and PTSA (3.1 mg, 0.016 mmol) was added. The mixture was stirredat r.t. for 48 hours. The reaction mixture was concentrated to an oilthen re-dissolved in EtOAc. The EtOAc layer was washed with saturatedNaHCO₃(aq), brine, dried with Na₂SO₄, filtered and concentrated to anoil. The crude mixture was purified by silica gel chromatography elutinga gradient of 0% to 100% EtOAc in heptane to give(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol as a white solid, 76 mg (79% yield, 80% pure).

To a suspension of(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol(76 mg, 80% pure) in 2-methyl-tetrahydrofuran (1 ml) at r.t. was added60% sodium hydride (26 mg). After 15 minutes methyl iodide (200 ul) wasadded. After 1 hour more methyl iodide (200 ul) was added and themixture was stirred at r.t. for 3 more hours. The reaction mixture wasquenched with saturated ammonium chloride (aq) then extracted withEtOAc. The EtOAc layer was washed with brine, dried with Na₂SO₄,filtered and concentrated to an oil. The crude oil was purified bysilica gel chromatography eluting with a gradient of 0% to 100% EtOAc inheptane to give(+/−)-7-((3aS,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidineas a colorless oil, 39 mg (39% yield).

LCMS-ESI(+): MH+=304, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (s, 1H),7.43 (d, J=3.7 Hz, 1H), 6.53 (d, J=3.7 Hz, 1H), 5.30 (ddd, J=2.6, 5.3,7.8 Hz, 1H), 4.84 (dd, J=2.1, 6.2 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 3.94(t, J=4.2 Hz, 1H), 3.41 (s, 3H), 2.80-2.65 (m, 4H), 2.24 (td, J=4.6,14.5 Hz, 1H), 1.54 (s, 3H), 1.30 (s, 3H).

Step 4: Synthesis of(+/−)-(1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-5), (1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-6) and(1R,2R,3R,5S)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-7)

A mixture of T-4 (39 mg, 0.13 mmol) and 50% aqueous TFA (800 ul) washeated to 60° C. for 2 hours. The reaction mixture was concentrated toan oil then purified by SFC (3HOP column) to give(+/−)-(1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-5) as a white solid, 25 mg (75% yield).

T-5: LCMS-APCI(+): MH+=264, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.61(s, 1H), 7.31 (d, J=3.7 Hz, 1H), 6.59 (d, J=3.4 Hz, 1H), 4.95 (q, J=8.6Hz, 1H), 4.54-4.39 (m, 1H), 4.23 (d, J=4.9 Hz, 1H), 3.87 (t, J=5.4 Hz,1H), 3.47 (s, 3H), 2.98-2.81 (m, 1H), 2.71 (s, 3H), 2.09 (ddd, J=5.1,9.0, 13.8 Hz, 1H).

T-5 was resolved by chiral SFC (Lux Cellulose-4 4.6×100 mm 3 u column,30% MeOH/DEA @120 bar, 4 mL/min) to give(1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-6) as a white solid, 6 mg (19% yield).

T-6: LCMS-APCI(+): MH+=264, ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.61 (s,1H), 7.60 (d, J=3.5 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 5.11-4.83 (m, 3H),4.40-4.26 (m, 1H), 3.91 (br. s., 1H), 3.61 (t, J=4.8 Hz, 1H), 3.31 (s,3H), 2.63 (s, 3H), 2.56 (td, J=8.0, 14.0 Hz, 1H), 1.77 (ddd, J=4.8, 9.1,13.8 Hz, 1H)

and(1R,2R,3R,5S)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(T-7) as a white solid, 6 mg (19% yield).

T-7: LCMS-APCI(+): MH+=264, 1H NMR (700 MHz, DMSO-d6) δ ppm 8.61 (s,1H), 7.60 (d, J=3.5 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 5.07-4.92 (m, 3H),4.38-4.25 (m, 1H), 3.91 (br. s., 1H), 3.66-3.52 (m, 1H), 3.31 (s, 3H),2.63 (s, 3H), 2.56 (td, J=8.1, 13.8 Hz, 1H), 1.76 (ddd, J=4.6, 8.9, 13.8Hz, 1H)

Example 62: (SchemeU)—(1S,2S,3S,5R)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-6) Example 63: (SchemeU)—(1R,2R,3R,5S)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-7)

Step 1: Synthesis of2-(((3aR,4S,6R,6aS)-6-((5-((E)-2-ethoxyvinyl)-6-methylpyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)benzonitrile.(U-1)

To a mixture of T-3 (181 mg, 0.54 mmol) and 2-fluorobenzonitrile (57.4ul, 65.4 mg, 0.54 mmol) in THF (1.8 ml, 0.3 M) at r.t. was added 60%sodium hydride (45.3 mg, 1.13 mmol). After stirring for 5 minutes thereaction mixture was heated to 70° C. for 6 hours. The reaction mixturewas cooled to r.t. then quenched with saturated NH₄Cl(aq), diluted withwater and extracted with EtOAc. The EtOAc layer was washed with brine,dried with MgSO4, filtered then concentrated to an oil. The crude oilwas purified by silica gel chromatography eluting with 0-100%EtOAc-Heptane to give U-1 as an amber oil, 210 mg (89% yield).

LCMS-ESI(+): MH+=437, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1H),7.68-7.49 (m, 2H), 7.19-6.98 (m, 2H), 6.47 (d, J=13.2 Hz, 1H), 5.45 (d,J=7.6 Hz, 1H), 5.41 (d, J=13.2 Hz, 1H), 4.82-4.69 (m, 4H), 3.86 (q,J=6.8 Hz, 2H), 2.70 (td, J=6.1, 15.0 Hz, 1H), 2.35 (s, 3H), 2.13 (d,J=15.2 Hz, 1H), 1.51 (s, 3H), 1.32 (s, 3H), 1.26 (t, J=7.0 Hz, 4H).

Step 2:2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)benzonitrile.(U-2)

A solution of U-1 (210 mg, 0.481 mmol in acetic acid (4.81 ml, 0.1 M)was heated to 110° C. for 19 hours. The reaction mixture wasconcentrated to an oil then purified by silica gel chromatographyeluting with 0-100% EtOAc-Heptane to give U-2 as a dark amber glass, 166mg (88% yield).

LCMS-ESI(+): MH+=391, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.79 (s, 1H),7.69 (d, J=3.4 Hz, 1H), 7.65-7.51 (m, 2H), 7.13 (d, J=8.6 Hz, 1H), 7.07(t, J=7.6 Hz, 1H), 6.66 (d, J=3.7 Hz, 1H), 5.48 (dd, J=3.2, 6.8 Hz, 1H),5.01 (d, J=4.6 Hz, 1H), 4.95 (dd, J=2.7, 6.1 Hz, 1H), 4.86 (d, J=5.9 Hz,1H), 3.06 (td, J=7.6, 14.7 Hz, 1H), 2.74 (s, 3H), 2.57 (d, J=14.9 Hz,1H), 1.62 (s, 4H), 1.34 (s, 4H).

Step 3: Synthesis of(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenyl)methanamine(U-3)

A mixture of U-2 (139 mg, 0.356 mmol) in ethanol (7.12 ml, 0.05 M) wasadded 28% NH₄OH (3 ml) and Raney Nickel (70 mg, 1.2 mmol). The mixturewas hydrogenated at 50 psi in a stainless steel bomb for 24 hours. Thereaction mixture was filtered through celite then the filtrate wasconcentrated to an oil and purified by silica gel chromatography elutingwith 0-100% MeOH in EtOAc to give U-3 as a colorless oil, 81 mg (58%yield).

LCMS-APCI(+): MH+=395, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.64 (s, 1H),7.62 (d, J=3.7 Hz, 1H), 7.34-7.23 (m, 2H), 7.12 (d, J=8.6 Hz, 1H), 6.96(t, J=7.5 Hz, 1H), 6.75 (d, J=3.7 Hz, 1H), 5.28 (dt, J=3.5, 7.0 Hz, 1H),5.19 (dd, J=3.4, 6.4 Hz, 1H), 4.94 (d, J=6.4 Hz, 1H), 4.87 (t, J=5.9 Hz,1H), 3.72 (br. s., 2H), 2.95 (td, J=7.0, 14.1 Hz, 1H), 2.73 (s, 3H),2.65-2.54 (m, 1H), 1.60 (s, 3H), 1.35 (s, 3H).

Step 4: Synthesis of tert-butyl(2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)carbamate (U-4) andtert-butyl(2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)carbamate (U-5)

A solution of the U-3 (81 mg, 0.21 mmol) in 50% TFA (aq) (600 ul) wasstirred at r.t for 16 hours. The reaction mixture was then concentratedto an oil. A mixture of the crude oil and Boc₂O (30.8 mg, 1.41 mmol) inDCM 30.8 mg, 0.141 mmol) was stirred at r.t. for 6 hours. The reactionmixture was concentrated then purified by silica gel chromatographyeluting with 40 to 100% EtOAc in heptane then 0-20% MeOH in EtOAc togive racemic mixture of U-4 and U-5 as a colorless oil, 73 mg. Theenantiomers were separated by chiral SFC (Chiralpak IC-3 4.6×100 mm 3 ucolumn, 30% MeOH @ 120 bar, 4 mL/min) to give U-4 (25.4 mg, 40% yield)and U-5 (24.4 mg, 38% yield) as white solids.

U-4: LCMS-ESI(+): MH+=455, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.52 (s,1H), 7.51 (br. s., 1H), 7.23-7.09 (m, 2H), 6.92 (d, J=8.1 Hz, 1H), 6.84(t, J=7.5 Hz, 1H), 6.64 (d, J=3.7 Hz, 1H), 5.15 (q, J=8.6 Hz, 1H),4.67-4.58 (m, 2H), 4.34-4.15 (m, 2H), 4.11 (d, J=4.4 Hz, 1H), 2.90 (ddd,J=7.3, 9.4, 14.5 Hz, 1H), 2.61 (s, 3H), 2.24-2.08 (m, 1H), 1.33 (s, 9H).[α]D22=+61.3° (c=0.1, MeOH).

U-5: LCMS-ESI(+): MH+=455, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.62 (s,1H), 7.61 (br. s., 1H), 7.33-7.17 (m, 2H), 7.02 (d, J=8.1 Hz, 1H), 6.94(t, J=7.3 Hz, 1H), 6.74 (d, J=3.7 Hz, 1H), 5.25 (q, J=9.0 Hz, 1H), 4.74(d, J=7.1 Hz, 2H), 4.43-4.25 (m, 2H), 4.21 (d, J=4.4 Hz, 1H), 3.00 (ddd,J=7.3, 9.5, 14.7 Hz, 1H), 2.71 (s, 3H), 2.38-2.12 (m, 1H), 1.43 (s, 9H).[α]D22=−86.1° (c=0.1, MeOH)

Step 5: Synthesis of(1S,2S,3S,5R)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-6)

A mixture of U-4 (24 mg, 0.053 mmol) and trifluoroacetic acid (120 mg,1.06 mmol) in DCM (0.176 ml, 0.3 M) was stirred at r.t. for 3 hours thenconcentrated to an oil and purified by SFC (ZymorSpher Pyridine Diol150×21.2 mm column with 20-40% MeOH @ 5%/min, 100 bar, 60 mL/min.) togive U-6 as a white solid, 6.54 mg (35% yield).

LCMS-APCI(+): MH+=355, 1H NMR (700 MHz, DMSO-d6) δ ppm 8.62 (s, 1H),7.66 (d, J=2.2 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H),7.07 (d, J=7.9 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H),5.12 (q, J=8.8 Hz, 1H), 4.61 (d, J=3.1 Hz, 1H), 4.06 (br. s., 1H),2.94-2.75 (m, 1H), 2.64 (s, 3H), 2.03 (t, J=9.7 Hz, 1H)

Step 6: Synthesis of(1R,2R,3R,5S)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-7)

U-7 was prepared in a similar manner to U-6 staring from U-5 to give awhite solid, 9 mg (50% yield).

LCMS-APCI(+): MH+=355, 1H NMR (700 MHz, DMSO-d6) δ ppm 8.63 (s, 1H),7.66 (d, J=3.5 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H),7.13 (d, J=8.4 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 6.72 (d, J=3.5 Hz, 1H),5.19-5.04 (m, 2H), 4.63 (d, J=4.4 Hz, 2H), 4.08 (d, J=4.4 Hz, 1H), 4.06(s, 2H), 2.87 (td, J=8.3, 14.2 Hz, 1H), 2.64 (s, 3H), 2.06 (ddd, J=4.0,9.5, 13.9 Hz, 1H)

Example 64 (SchemeV)—2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile(V-1) Example 65 (SchemeV)—2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile(V-2)

Step 1: Synthesis of2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile(V-1) and2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile(V-2)

V-1 (9.5 mg, 47% yield) and V-2 (9.4 mg, 47% yield) were prepared fromU-2 in a similar manner to step 5 in Scheme U.

V-1: LCMS-ESI(+): MH+=351, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.68 (br.s., 1H), 7.75 (d, J=3.7 Hz, 1H), 7.71-7.60 (m, 2H), 7.30 (d, J=8.6 Hz,1H), 7.12 (t, J=7.6 Hz, 1H), 6.82 (d, J=3.7 Hz, 1H), 5.36 (q, J=8.5 Hz,1H), 4.89 (d, J=6.1 Hz, 1H), 4.71 (dd, J=4.6, 8.3 Hz, 1H), 4.23 (d,J=4.2 Hz, 1H), 3.16-3.01 (m, 1H), 2.75 (s, 3H), 2.18 (ddd, J=2.4, 7.6,14.7 Hz, 1H).

V-2: LCMS-ESI(+): MH+=351, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.73 (br.s., 1H), 7.79 (d, J=3.7 Hz, 1H), 7.72-7.61 (m, 1H), 7.31 (d, J=8.6 Hz,1H), 7.12 (t, J=7.6 Hz, 1H), 6.87 (d, J=3.7 Hz, 1H), 5.43-5.31 (m, 1H),4.90 (d, J=5.9 Hz, 1H), 4.72 (dd, J=4.6, 8.6 Hz, 1H), 4.23 (d, J=4.4 Hz,1H), 3.16-3.01 (m, 1H), 2.77 (s, 2H), 2.19 (ddd, J=2.3, 7.6, 14.8 Hz,1H)

Example 66 (SchemeW)—(1S,2S,3S,5R)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(W-5) Example 67 (SchemeW)—(1R,2R,3R,5S)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol.(W-6)

Step 1: Synthesis of(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol(W-1)

A mixture of T-3 (111 mg, 0.331 mmol) and trifluoroacetic acid (127 ul,1.65 mmol) in acetone (3.31 ml, 0.1 M) was heated to 60° C. for 43hours. The reaction mixture was concentrated to an oil then dissolved inEtOAc. The EtOAc layer was washed with saturated NaHCO₃(aq), brine,dried with Na₂SO₄, filtered and concentrated to an oil. The crudemixture was purified by silica gel chromatography eluting a gradient of0% to 100% EtOAc in heptane to give W-1 as a white solid, 76 mg (79%yield, 80% pure).

Step 1: Synthesis of2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzonitrile(W-2)

To a mixture of W-1 (67.1 mg, 0.2 mmol) and 2,5-difluorobenzonitrile(55.0 mg, 0.395 mmol 55.0 uL) in THF (1.01 mL, c=0.3 M) at r.t. wasadded 60% sodium hydride (24.3 mg, 0.608 mmol). After stirring for 3minutes the reaction mixture was heated to 70° C. for 6 hours thenquenched with saturated NH₄Cl(aq) then diluted with EtOAc and water. TheEtOAc layer was washed with brine, dried with Na₂SO₄ filtered thenconcentrated to an oil. The oil was purified by silica gelchromatography eluting with 0-100% EtOAc in heptane to give W-2 as awhite foam, 101 mg (81% yield).

LCMS-ESI(+): MH+=409, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 3H)1.61 (s, 3H) 2.59 (d, J=15.41 Hz, 1H) 2.78 (s, 3H) 3.05 (dt, J=15.16,7.34 Hz, 1H) 4.84 (d, J=6.36 Hz, 1H) 4.86-4.92 (m, 1H) 5.04 (d, J=4.40Hz, 1H) 5.35-5.53 (m, 1H) 6.68 (d, J=3.18 Hz, 1H) 7.11 (dd, J=9.78, 3.67Hz, 1H) 7.32 (d, J=7.58 Hz, 2H) 7.66 (br. s., 1H) 8.80 (s, 1H).

Step 2: Synthesis of tert-butyl(2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzyl)carbamate (W-3)and tert-butyl(2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzyl)carbamate(W-4)

To a mixture of W-2 (101 mg, 0.247 mmol) in ethanol (7.0 mL) was added28% ammonium hydroxide (3.0 mL) and Raney Nickel (70 mg, 1.2 mmol). Themixture was hydrogenated at 50 psi in a stainless steel bomb for 24hours. The reaction mixture was filtered through celite thenconcentrated to a foam.

To this crude amine was added boc anhydride (54 mg, 0.247 mmol) in DCM(3 ml, 0.3 M) and stirred at r.t. for 2 hours. This was concentrated toa foam and purified by silica gel chromatography to give a racemicmixture of W-3 and W-4 as a colorless oil, 104 mg 982% yield). Theenantiomers were separated by chiral SFC (Chiralpak AS-3 4.6×100 mm 3 ucolumn, 8% MeOH+10 mM NH3 @ 120 bar, 4 mL/min) to give W-3 (34.2 mg, 27%yield) and W-4 (35.9 mg, 28% yield) as white solids.

W-3: LCMS-ESI(+): MH+=513, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm8.86-8.76 (m, 1H), 7.45 (br. s., 1H), 7.02 (d, J=8.6 Hz, 1H), 6.95 (d,J=5.1 Hz, 2H), 6.67 (d, J=3.2 Hz, 1H), 5.35 (br. s., 1H), 5.07 (d, J=3.7Hz, 1H), 4.89-4.71 (m, 3H), 4.21 (br. s., 1H), 2.98 (td, J=7.2, 14.7 Hz,1H), 2.81 (s, 3H), 2.54 (d, J=15.2 Hz, 1H), 1.61 (s, 3H), 1.50-1.38 (m,10H), 1.34 (s, 3H), [α]D22=+28.2° (c=0.1, MeOH)

W-4: LCMS-ESI(+): MH+=513 ˜80% pure.

Step 3: Synthesis of(1S,2S,3S,5R)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. (W-5)

A mixture of W-3 (34 mg, 0.066 mmol) in a mixture of 50% TFA(aq) (0.4ml) was stirred at r.t. for 3 hours then concentrated and purified bySFC (ZymorSpher Pyridine Diol 150×21.2 mm column with 20-40% MeOH @5%/min, 100 bar, 60 mL/min.) to give W-5 as a white solid, 16.5 mg (67%yield).

LCMS-ESI(+): MH+=373, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 7.65(d, J=3.7 Hz, 1H), 7.28 (dd, J=2.6, 9.2 Hz, 1H), 7.21-7.03 (m, 2H), 6.72(d, J=3.4 Hz, 1H), 5.19-4.98 (m, 2H), 4.69-4.48 (m, 2H), 4.06 (d, J=4.6Hz, 1H), 4.00 (s, 2H), 2.95-2.76 (m, 1H), 2.64 (s, 3H), 2.04 (ddd,J=4.0, 9.5, 13.8 Hz, 1H)

Step 4: Synthesis of(1R,2R,3R,5S)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. (W-6)

W-6 was prepared from W-4 in a similar manner to step 3 in Scheme W togive a white solid, 17.2 mg (70% yield).

LCMS-ESI(+): MH+=373, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 7.65(d, J=3.7 Hz, 1H), 7.28 (dd, J=2.6, 9.2 Hz, 1H), 7.21-7.07 (m, 2H), 6.72(d, J=3.4 Hz, 1H), 5.18-5.02 (m, 2H), 4.69-4.54 (m, 2H), 4.06 (d, J=4.6Hz, 1H), 4.01 (s, 2H), 2.94-2.74 (m, 1H), 2.64 (s, 3H), 2.04 (ddd,J=4.2, 9.5, 13.7 Hz, 1H).

Example 68 (SchemeX)—2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzonitrile(X-2) Example 69 (SchemeX)—2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzonitrile(X-3)

Step 1: Synthesis of2-(((3aR,4S,6R,6aS)-6-((5-((Z)-2-ethoxyvinyl)-6-methylpyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzonitrile.(X-1)

A mixture of T-3 (67.1 mg, 0.2 mmol) and O-fluorobenzonitrile (25.5 ul,0.240 mmol) in THF (0.67 ml, 0.3 M) at r.t. was added 60% sodium hydride(16.8 mg, 0.42 mmol). The mixture was then heated to 70° C. in amicrowave reactor for 30 minutes. The reaction mixture was quenched withsaturated NH₄Cl(aq) then diluted with water and extracted with EtOAc.The EtOAc was washed with brine, dried with Na₂SO₄, filtered andconcentrated to an oil then purified by silica gel chromatographyeluting with 0-100% EtOAc/Heptane to give X-1 as an amber oil, 58 mg(64% yield).

LCMS-ESI(+): MH+=455, ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (s, 1H),7.35-7.28 (m, 2H), 7.16-7.06 (m, 1H), 6.47 (d, J=13.2 Hz, 1H), 5.43 (d,J=7.3 Hz, 1H), 5.39 (d, J=13.2 Hz, 1H), 4.81-4.65 (m, 4H), 3.87 (q,J=7.0 Hz, 2H), 2.69 (td, J=6.1, 14.9 Hz, 1H), 2.34 (s, 3H), 2.11 (d,J=14.9 Hz, 1H), 1.50 (s, 3H), 1.31 (s, 2H), 1.27 (t, J=7.0 Hz, 3H).

Step 2: Synthesis of2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzonitrile(X-2) and2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzonitrile(X-3)

A mixture of the X-1 (58 mg, 0.13 mmol) and 1N HCl(aq) (255 ul, 0.255mmol) in 1,4-dioxane (0.382 ml, 0.15 M) was stirred at r.t. for 24hours. Trifluoroacetic acid (200 ul) was added and the mixture wasstirred at r.t for 48 hours then heated to 60° C. for 6 hours. Thereaction mixture was concentrated to an oil then partitioned betweenEtOAc and and water. Saturated NaHCO₃(aq) was added and the EtOAc layerwas washed with brine, dried with Na₂SO₄, filtered then concentrated toa white solid, 44 mg. The enantiomers were separated by chiral SFC (LuxCellulose-2 4.6×100 mm 3 u column, 30% MeOH @ 120 bar, 4 mL/min) to giveX-2 (17 mg, 36% yield) and X-3 (16.2 mg, 35% yield) as white solids.

X-2: LCMS-ESI(+): MH+=369, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H),7.79 (dd, J=3.1, 8.2 Hz, 1H), 7.70 (d, J=3.4 Hz, 1H), 7.65-7.51 (m, 2H),7.40 (dd, J=4.2, 9.3 Hz, 1H), 6.76 (d, J=3.4 Hz, 1H), 5.41 (br. s., 1H),5.15 (q, J=8.9 Hz, 1H), 4.77 (br. s., 1H), 4.53 (br. s., 1H), 4.05 (br.s., 1H), 2.97-2.75 (m, 1H), 2.65 (s, 3H), 2.11-1.93 (m, 1H),[α]D22=+47.3° (c=0.1, MeOH).

X-3: LCMS-ESI(+): MH+=369, ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (d,J=3.4 Hz, 1H), 7.51 (dd, J=2.9, 7.6 Hz, 1H), 7.47-7.38 (m, 1H), 7.32(dd, J=4.0, 9.2 Hz, 1H), 6.80 (d, J=3.4 Hz, 1H), 5.33 (q, J=8.6 Hz, 1H),4.85 (br. s., 1H), 4.71 (dd, J=4.8, 8.2 Hz, 1H), 4.22 (d, J=3.9 Hz, 1H),3.12-2.97 (m, 1H), 2.74 (br. s., 3H), 2.26-2.12 (m, 1H), [α]D22=−53.5°(c=0.1, MeOH).

Example 70 (SchemeY)—2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzamide(Y-3)

Step 1—Synthesis of2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzonitrile(Y-1)

To a suspension of X-2 (4 g, 9.8 mmol) in dimethoxypropane (60 mL)/DMF(20 mL) was added TsOH.H₂O (2990 mg, 15.75 mmol) at rt (20° C.). Theresulting solution was stirred at rt (20° C.) for 24 hrs. The mixturewas purified directly by silica gel chromatography eluted with EtOAc inpetroleum ether from 0 to 100% to afford Y-1 (2.2 g, 55%) as a whitesolid. LCMS 409 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H), 7.60(d, J=3.8 Hz, 1H), 7.33-7.25 (m, 2H), 7.15-7.06 (m, 1H), 6.63 (d, J=3.5Hz, 1H), 5.44 (ddd, J=2.5, 5.0, 7.8 Hz, 1H), 5.02 (dd, J=2.3, 6.0 Hz,1H), 4.90-4.85 (m, 1H), 4.82 (d, J=6.3 Hz, 1H), 3.04 (ddd, J=6.8, 8.0,15.1 Hz, 1H), 2.72 (s, 3H), 2.63-2.53 (m, 1H), 1.60 (s, 3H), 1.33 (s,3H)

Step 2—Synthesis of2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzamide(Y-2)

To a solution of Y-1 (50 mg, 0.12 mmol) in DMSO (0.25 mL) was addedK₂CO₃ (20 mg, 0.15 mmol), followed by H₂O₂(0.25 mL) drop-wise atice-water, then the reaction can be warmed to room temperature for 2 h,in which gas was observed. To the reaction mixture was added water andextracted with EtOAc two times. The organic layer was dried over sodiumsulfate, filtered, and the residue was purified by prep-TLC to give Y-2(36 mg, 69%) and used as is in the next step.

Step 3—Synthesis of2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzamide(Y-3)

To a suspension of Y-2 (42 mg, 0.1 mmol) in H₂O (0.3 mL) was added TFA(0.3 mL) drop-wise at 0° C. Then the reaction mixture was stirred atroom temperature (20° C.) for 16 h. The reaction was then adjusted to pH7 with 20% K₂CO₃ in which solid was formed, then filtered, and washedwith water and MTBE. The solid was dried to give Y-3 (32 mg, 84%). LCMS387 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.62-7.65 (m,1H), 7.60 (d, J=3.8 Hz, 1H), 7.24-7.30 (m, 2H), 6.75 (d, J=3.5 Hz, 1H),5.16 (q, J=8.8 Hz, 1H), 4.82-4.87 (m, 2H), 4.27 (d, J=4.8 Hz, 1H), 3.02(ddd, J=14.6, 9.6, 7.4 Hz, 1H), 2.73 (s, 3H), 2.42 ppm (ddd, J=13.7,9.2, 4.3 Hz, 1H)

Example 71 (SchemeZ)—(1S,2S,3S,5R)-3-(2-((dimethylamino)methyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(8)

Step 1—Synthesis of(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)methanamine(Z-1)

A mixture of Y-1 (500 mg, 1.22 mmol) and Ra—Ni (100 mg) in EtOH (30mL)/NH₃.H₂O (3 mL) was de-gassed with H₂ four times. The mixture wasstirred at rt (20° C.) under H₂ balloon for 20 hrs then allowed to standat rt for 20 hrs. The mixture was filtered and concentrated in vacuo toafford Z-1 (510 mg, >99%) as a light yellow gum. LCMS [M+1] 413; ¹H NMR(400 MHz, CDCl₃) δ ppm 8.79 (s, 1H), 7.37 (d, J=3.5 Hz, 1H), 7.05 (dd,J=2.4, 8.7 Hz, 1H), 6.99-6.88 (m, 2H), 6.58 (d, J=3.8 Hz, 1H), 5.33(ddd, J=2.6, 5.5, 8.0 Hz, 1H), 5.05 (dd, J=2.9, 6.1 Hz, 1H), 4.88-4.80(m, 1H), 4.80-4.75 (m, 1H), 3.76 (br. s., 2H), 3.06-2.89 (m, 1H), 2.73(s, 3H), 2.62-2.47 (m, 1H), 1.61 (s, 3H), 1.34 (s, 3H)

Step 2—Synthesis of1-(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)-N,N-dimethylmethanamine(Z-2)

A mixture of Z-1 (100 mg, 0.24 mmol), 37% CH₂O (59 mg, 0.73 mmol) andNaBHOAc₃ (206 mg, 0.970 mmol) in THF (2 mL) was stirred at rt for 2 hrs.The mixture was poured into NaHCO₃ aq (10 mL) and extracted with EtOAc(10 mL×3). The extract was washed with brine (10 mL), dried over Na₂SO₄and concentrated in vacuo to afford Z-2 (100 mg, 94%) as a colorlessgum.

LCMS 441 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.79 (s, 1H), 7.49 (d,J=3.8 Hz, 1H), 7.14-7.08 (m, 1H), 7.01-6.86 (m, 2H), 6.55 (d, J=3.5 Hz,1H), 5.37 (t, J=2.8 Hz, 1H), 5.02 (d, J=4.0 Hz, 1H), 4.83 (d, J=6.3 Hz,1H), 4.77 (dd, J=3.3, 5.8 Hz, 1H), 3.33 (s, 2H), 2.97 (d, J=8.0 Hz, 1H),2.73 (s, 3H), 2.54 (d, J=13.8 Hz, 1H), 2.23 (s, 6H), 1.60 (s, 3H), 1.33(s, 3H)

Step 3—Synthesis of(1S,2S,3S,5R)-3-(2-((dimethylamino)methyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(Z-3)

To TFA/H₂O (1 mL/2 mL) was added Z-2 (100 mg, 0.23 mmol) at rt. Themixture was stirred at rt for 1 hr. The mixture was poured into 20%K₂CO₃ (10 mL). The mixture was washed saturated with NaCl and extractedwith EtOAc/THF (20 mL/20 mL) twice. The extract was washed withconcentrated in vacuo. The residue was dissolved in CH₃CN/H₂O (10 mL/50mL) and lyophilized to afford Z-3 (70 mg, 77%) as a white solid. LCMS404 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (s, 1H), 7.69 (d, J=3.8Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.05 (d, J=5.5 Hz, 2H), 6.72 (d, J=3.5Hz, 1H), 5.36 (br. s., 1H), 5.16-5.09 (m, 2H), 4.60-4.49 (m, 2H), 4.01(d, J=3.3 Hz, 1H), 3.57-3.48 (m, 1H), 3.44 (br. s., 1H), 2.90-2.78 (m,1H), 2.63 (s, 3H), 2.23 (s, 6H), 1.96-1.86 (m, 1H)

Example 72 (SchemeAA)—(1S,2S,3S,5R)-3-(4-fluoro-2-((methylamino)methyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(11)

Step 1—Synthesis of tert-butyl(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo [2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzyl)carbamate(AA-1)

To a solution of Z-1 (140 mg, 0.34 mmol) and Et₃N (34 mg, 0.34 mmol) inDCM (5 mL) was added Boc₂O (74 mg, 0.34 mmol) at rt (20° C.). Themixture was stirred at rt (20° C.) for 1 hr.

The mixture was purified by silica gel chromatography eluted with EtOACin petroleum ether from 0 to 100% to afford AA-1 (140 mg, 81%) as acolorless oil. LCMS 513 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.78 (s,1H), 7.33 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.93 (d, J=5.2 Hz, 2H), 6.58(d, J=3.6 Hz, 1H), 5.30-5.28 (m, 1H), 5.06-5.05 (m, 1H), 4.81 (d, J=6Hz, 2H), 4.76-4.75 (m, 1H), 4.18 (d, J=3.2 Hz, 1H), 2.98-2.90 (m, 1H),2.71 (s, 3H), 2.54-2.50 (m, 1H), 1.55 (s, 3H), 1.44 (s, 9H), 1.24 (s,3H)

Step 2—Synthesis of tert-butyl(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo [2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzyl)(methyl)carbamate(AA-2)

To a solution of AA-1 (140 mg, 0.27 mmol) in dry DMF (3 mL) was added60% NaH (16.4 mg, 0.41 mmol) at rt (0° C.). The mixture was stirred atrt (20° C.) for 1 hr. CH₃I (56 mg, 0.4 mmol) was added to the mixtureand stirred at rt (20° C.) for 20 hrs. The mixture was poured into NH₄Claq (10 mL) and extracted with EtOAc (5 mL×3). The extract was washedwith brine (5 mL), dried over Na₂SO₄ and concentrated in vacuo to affordcrude material (200 mg) as a brown oil which was purified by silica gelchromatography eluted with EtOAc in petroleum ether from 0 to 100% toafford AA-2 (100 mg, 70%) as a colorless gum. LCMS 527 [M+1]

Step 3—Synthesis of(1S,2S,3S,5R)-3-(4-fluoro-2-((methylamino)methyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(AA-3)

To TFA/H₂O (1 mL/2 mL) was added AA-2 (89 mg, 0.169 mmol) at rt. Themixture was stirred at rt for 2 hrs, then poured into 20% K₂CO₃ aq (5mL). The mixture was extracted with EtOAc (10 mL×3). The extract waswashed with brine (10 mL×2), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was dissolved in CH₃CN/H₂O (4 mL/10mL) and lyophilized to afford AA-3 (55 mg, 84%) as a white solid. LCMS387 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1H), 7.67 (d, J=3.8Hz, 1H), 7.23-7.14 (m, 1H), 7.08-6.98 (m, 2H), 6.73 (d, J=3.8 Hz, 1H),5.12 (q, J=9.1 Hz, 2H), 4.57 (br. s., 2H), 4.02 (d, J=4.8 Hz, 1H), 3.71(s, 2H), 2.92-2.77 (m, 1H), 2.65 (s, 3H), 2.34 (s, 3H), 2.03-1.93 (m,1H)

Example 73 (SchemeBB)—(1S,2S,3S,5R)-3-(4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(BB-4)

Step 1: Synthesis oftert-butyl-((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)-carbonate(BB-2)

Vial A:

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was addedTris(benzylideneacetone)dipalladium(0)chloroform adduct (78.7 mg, 0.0760mmol) and (S,S)-DACH-Naphthyl Trost Ligand (MFCD02684552) (180 mg, 0.228mmol). The vial was vacuum purged with argon under dynamic vacuum andDCE (7.5 mL), which had been sparged with argon for 30 minutes. Thesolution was stirred for 30 minutes at rt at which point a bright orangesolution of ligated catalyst was obtained. At this stage Vial B wasprepared.

Vial B:

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was added4-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-1) (506 mg, 3.8 mmol),di-tert-butyl-((1R,3S)-cyclopent-4-ene-1,3-diyl)-bis(carbonate) (BB-1)(prepared as reported in J. Am. Chem. Soc. 2006, 128, 6054-6055) (1.37g, 4.56 mmol), and cesium carbonate (1.36 g, 4.18 mmol). The vial wasvacuum purged with argon under dynamic vacuum and DCE (7.5 mL), whichhad been sparged with argon for 30 minutes, was added followed by theaddition of the contents of Vial A via airtight syringe. The reactionwas stirred under argon at rt for 48 hours. The reaction was transferredto a separatory funnel with DCM. The solution was washed with 2 portionswater and 1 portion brine. A small amount of 1M HCl was used todissipate the emulsion in the last wash. The organic phase was dried(MgSO₄), filtered, and concentrated under vacuum. The crude residue waspurified via flash column chromatography (40 g SiO₂, Isco, 100% Hept. to100% EtOAc, 20 mL fractions) to afford the compound BB-2 (814 mg,68%, >99% ee) as a brown gum which solidified upon standing. LCMS[M+H]=316 observed; Chiral LCMS (Chiralcel OJ-3 4.6×100 mm 3p column, 4%MeOH+10 nM NH₃ @ 120 bar, 4 mL/min) peak 1 @ 0.63 min., peak 2 @ 0.77min., observed major peak @ 0.65 min, 99.8:0.2% by MS area; ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.78 (s, 1H), 7.32-7.22 (m, 1H), 6.60 (d, J=3.7Hz, 1H), 6.35-6.23 (m, 1H), 6.10 (d, J=5.4 Hz, 1H), 6.00 (br. s., 1H),5.66-5.57 (m, 1H), 3.21-3.07 (m, 1H), 2.75 (s, 3H), 1.89 (d, J=14.9 Hz,1H), 1.57-1.46 (m, 9H).

Step 2: Synthesis of7-((1R,4S)-4-(4-fluorophenoxy)cyclopent-2-en-1-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (BB-3)

To a scintillation vial, equipped with a magnetic stirbar, was addedBB-2 (56.8 mg, 0.180 mmol), 4-fluorophenol (22.2 mg, 0.198 mmol),diphenylphosphinopropane (dppp) (4.5 mg, 0.0108 mmol),tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (4.7 mg,0.0045 mmol), and cesium carbonate (64.6 mg, 0.198 mmol). The vial waspurged with argon under dynamic vacuum followed by the addition of DCE(0.9 mL) which had been sparged with argon for 30 minutes. The reactionwas stirred at rt under argon for 2.5 hours. The reaction was taken upwith DCM and loaded directly onto a pre-packed silica column. The cruderesidue was purified via flash column chromatography (12g SiO2, Isco,100% Hept. to 100% EtOAc, 9 mL fractions) to afford the compound BB-3(38.8 mg, 70% yield) as a colorless gum. LCMS [M+H]=310 observed; ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.77 (s, 1H), 7.34 (d, J=3.55 Hz, 1H),6.92-7.04 (m, 2H), 6.80-6.92 (m, 2H), 6.57 (d, J=3.55 Hz, 1H), 6.37 (d,J=5.38 Hz, 1H), 6.14 (d, J=4.03 Hz, 1H), 5.97-6.09 (m, 1H), 5.17-5.34(m, 1H), 3.02-3.18 (m, 1H), 2.56-2.91 (m, 3H), 1.97 (td, J=3.35, 14.70Hz, 1H).

Step 3: Synthesis of(1S,2S,3S,5R)-3-(4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(BB-4)

To a scintillation vial, equipped with a magnetic stirbar and containingBB-3 (38.8 mg, 0.125 mmol), was added DCM (0.73 mL) and water (0.03 mL).To the solution was added 4-Methylmorpholine-N-oxide (NMO) (44.1 mg,0.376 mmol) followed by the dropwise addition of osmium tetraoxide (32μL, 0.005 mmol) as a 4 wt % solution in water. The reaction was stirredat rt for 8 hours. The reaction was quenched with 1M NaHSO₃ aq., stirredfor 30 minutes and transferred to a separatory funnel with DCM. Thesolution was further diluted with water and the product was extractedwith 4 portions of a 3:1 mixture of CHCl₃/i-PrOH. The combined organicextracts were dried (MgSO4), filtered, and concentrated under vacuum toafford the crude product as a white solid. The crude residue waspurified via preparative HPLC (Lux Cellulose-1 4.6×100 mm 3p column, 15%MeOH @ 120 bar, 4 mL/min) to afford the compound BB-4 (30.4 mg,71%, >99% de) as a white solid. LCMS [M+H]=344 observed; [α]²²_(D)=−36.0° (c=0.1, MeOH); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.61 (s,1H), 7.58 (d, J=3.67 Hz, 1H), 6.94-7.09 (m, 4H), 6.75 (d, J=3.67 Hz,1H), 5.27 (q, J=8.64 Hz, 1H), 4.58-4.68 (m, J=3.67 Hz, 2H), 4.17 (d,J=4.89 Hz, 1H), 2.96 (ddd, J=7.15, 9.32, 14.46 Hz, 1H), 2.71 (s, 3H),2.09 (ddd, J=3.85, 8.53, 14.03 Hz, 1H). 19F NMR (377 MHz, METHANOL-d4) δppm=−125.65 (s, 1F).

Examples 74-77 were prepared using the chemistry depicted in Scheme BBand employing the appropriate commercial Phenol reagent for step 2.

Example 74: 2,6-difluorophenol

362 LCMS [M + 1] (1S,2S,3S,5R)-3-(2,6- difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,METHANOL-d4) δ ppm 8.64 (s, 1H), 7.70 (d, J = 4.02 Hz, 1H), 7.18-7.02(m, 3H), 6.82 (d, J = 3.51 Hz, 1H), 5.39-5.31 (m, 1H), 4.75 (m, 1H),4.68 (m, 1H), 4.23 (m, 1H), 3.03- 2.94 (m, 1H), 2.75 (s, 3H), 2.19 (dd,J = 14.8, 5.3 Hz, 1H). Example 75: 4-fluoro-2- methylphenol

358 LCMS [M + 1] (1S,2S,3S,5R)-3-(4-fluoro-2-methylphenoxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H),7.59 (d, J = 3.8 Hz, 1H), 6.96 (td, J = 9.5, 4.0 Hz, 2H), 6.85-6.91 (m,1H), 6.78 (d, J = 3.5 Hz, 1H), 5.29 (q, J = 8.8 Hz, 1H), 4.64- 4.73 (m,2H), 4.21 (d, J = 4.5 Hz, 1H), 3.01 (ddd, J = 14.6, 9.5, 7.0 Hz, 1H),2.73 (s, 3H), 2.31 (s, 3H), 2.16 ppm (ddd, J = 14.5, 8.5, 3.4 Hz, 1H)Example 76 8-hydroxy-3,4- dihydroisoquinolin- 1(2H)-one

395 LCMS [M + 1] 8-(((1S,2S,3S,4S)-2,3- dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.60 (s,1H), 7.97 (d, J = 4.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.08 (d, J =8.8 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1H), 5.47-5.33 (m, 1H), 4.83-4.71 (m, 2H), 4.24 (d, J = 3.8 Hz, 1H), 3.42 (t, J =6.5 Hz, 2H), 3.06- 2.98 (m, 1H), 2.97-2.90 (m, 2H), 2.71 (s, 3H),2.11-2.02 (m, 1H) Example 77 isoquinolin-8-ol

377 LCMS [M + 1] (1S,2S,3S,5R)-3-(isoquinolin- 8-yloxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.69 (br s, 1H), 8.62 (s, 1H), 8.56 (br d, J = 4.5 Hz,1H), 7.83 (br d, J = 5.5 Hz, 1H), 7.79 (d, J = 3.5 Hz, 1H), 7.72 (t, J =8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.76(d, J = 3.5 Hz, 1H), 5.50 (br s, 1H), 5.20 (q, J = 1.0 Hz, 2H),4.89-4.83 (m, 1H), 4.72-4.66 (m, 1H), 4.18 (br d, J = 4.3 Hz, 1H), 3.02-2.91 (m, 1H), 2.66 (s, 3H), 2.24- 2.14 (m, 1H)

Example 78 (SchemeCC)—(1S,2S,3S,5R)-3-((6-chloro-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(CC-3)

Step 1—Synthesis of tert-butyl8-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(CC-1)

To a mixture of BB-2 (600 mg, 1.9 mmol) and tert-butyl8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (474 mg, 1.9 mmol),Cs₂CO₃ (682 mg, 2.09 mmol) and DPPP (47.1 mg, 0.11 mmol) in DCE (15 mL)was sparged with N₂ for 40 min. To the mixture was added Pd₂(dba)₃.CHCl₃(49 mg, 0.048 mmol) under N₂. The reaction was sparged with N₂ for 5 minthen stirred at rt (20° C.) under N₂ for 40 min. The mixture waspurified immediately (solution purified directly) by silica gelchromatography eluted with petroleum ether/EtOAc=8/1 to 1/1 thenDCM/MeOH=12/1 to afford CC-1 (735 mg, 87%) as a yellow gum. LCMS [M+1]447; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H), 7.33 (d, J=3.5 Hz, 1H),7.13 (t, J=7.9 Hz, 1H), 6.79-6.72 (m, 2H), 6.62-6.52 (m, 1H), 6.44-6.33(m, 1H), 6.21-6.11 (m, 1H), 6.09-6.01 (m, 1H), 5.41-5.33 (m, 1H),4.71-4.40 (m, 2H), 3.71-3.48 (m, 2H), 3.22-3.12 (m, 1H), 2.82 (br. s.,2H), 2.73 (s, 3H), 1.98 (d, J=15.1 Hz, 1H), 1.51 (s, 9H)

Step 2—Synthesis of tert-butyl8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(CC-2)

To a mixture of CC-1 (730 mg, 1.63 mmol) in DCM (15 mL)/H₂O (0.5 mL) wasadded NMO (575 mg, 4.9 mmol) and OsO₄ (4% in t-BuOH, 832 mg, 0.12 mmol).The mixture was stirred at rt (25° C.) for 3 hrs. Na₂SO₃ (500 mg) andwater (20 mL) was added. The mixture was stirred at rt for 1 hr then themixture was filtered. The filtrate was diluted with water (50 mL) andextracted with EtOAc (50 mL×2). The extract washed with brine (50 mL),dried over Na₂SO₄ and concentrated in vacuo and purified with silica gelchromatography eluted with MeOH in DCM from 0 to 10% to afford CC-2 (560mg, 71%) as a white solid. LCMS [M+1] 481; ¹H NMR (400 MHz, CDCl₃) δ ppm8.67 (s, 1H), 7.24 (d, J=3.8 Hz, 1H), 7.18 (t, J=7.9 Hz, 1H), 6.90 (d,J=8.0 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 5.08-4.94(m, 1H), 4.87-4.76 (m, 1H), 4.61-4.39 (m, 3H), 4.37-4.28 (m, 1H),3.76-3.55 (m, 2H), 3.46-3.31 (m, 1H), 3.20-3.04 (m, 1H), 2.86-2.79 (m,2H), 2.73 (s, 3H), 2.48-2.30 (m, 1H), 1.48 (s, 9H)

Step 3—Synthesis of(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(CC-3)

To a solution of CC-2 (560 mg, 1.17 mmol) in DCM (15 mL) was added TFA(4.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour.The reaction mixture was evaporated and dissolved in water (30 mL) andK₂CO₃ (1 g) was added. The mixture was diluted with brine (30 mL) andextracted with EtOAc/THF (1/1, 30 mL×3). The extract was washed withbrine (30 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuoto afford CC-3 (400 mg, 90%) as a white solid. LCMS [M+1] 381; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.64 (s, 1H), 7.62 (d, J=3.8 Hz, 1H), 7.11-7.02(m, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.73 (d, J=3.5 Hz, 1H), 6.68 (d, J=7.5Hz, 1H), 5.33 (br. s., 1H), 5.19-5.08 (m, 2H), 4.56 (br. s., 2H), 3.99(br. s., 1H), 3.85 (s, 2H), 2.93 (t, J=5.8 Hz, 2H), 2.90-2.81 (m, 1H),2.70-2.66 (m, 2H), 2.65 (s, 3H), 1.98-1.86 (m, 1H)

Examples 79 & 80 were prepared using the chemistry depicted in Scheme CCand employing the appropriate commercial NBoc-protected phenol reagentfor step 1.

Example 79 tert-butyl 4- hydroxyisoindoline-2- carboxylate

367 LCMS [M + 1] (1S,2S,3S,5R)-3-(2,3-dihydro-1H-isoindol-4-yloxy)-5-(4-methyl-7H- pyrrolo[2;3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H),8.43-8.33 (m, 1H), 7.59 (d, J = 3.5 Hz, 1H), 7.45- 7.36 (m, 1H),7.13-7.08 (m, 1H), 7.07-7.01 (m, 1H), 6.77 (d, J = 3.8 Hz, 1H),5.28-5.19 (m, 1H), 4.82- 4.78 (m, 1H), 4.76-4.71 (m, 1H), 4.67 (d, J =4.8 Hz, 4H), 4.24 (d, J = 3.8 Hz, 1H), 3.08-2.94 (m, 1H), 2.73 (s, 3H),2.28-2.15 (m, 1H) Example 80 tert-butyl 5-hydroxy- 3,4-dihydroisoquinoline- 2(1H)-carboxylate

381 LCMS [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (s,1H), 7.64 (d, J = 3.5 Hz, 1H), 7.26-7.18 (m, 1H), 6.99 (d, J = 8.0 Hz,1H), 6.82 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 3.5 Hz, 1H), 5.40 (br. s.,1H), 5.19-5.08 (m, 2H), 4.66-4.54 (m, 2H), 4.22 (s, 2H), 4.02 (br. s.,1H), 2.96-2.83 (m, 3H), 2.65 (s, 3H), 2.01-1.90 (m, 1H)

Example 81 (SchemeDD)—(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]cyclopentane-1,2-diol(DD-1)

Step 1: Synthesis of(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]cyclopentane-1,2-diol(DD-1)

A mixture of compound Example 80 (42 mg, 0.11 mmol), 37% CH₂O (26.9 mg,0.331 mmol) and NaBHOAc₃ (93.6 mg, 0.442 mmol) in THF (1.2 mL) wasstirred at rt for 2 hrs. The mixture was poured into NaHCO₃ aq (10 mL)and extracted with EtOAc (20 mL×4). The extract was dried over Na₂SO₄and concentrated in vacuo to afford the residue (50 mg) as a white solidwhich was purified by prep-TLC (DCM:MeOH=10:1 with NH₃.H₂O) to give DD-1(35 mg, 80%) as a white solid. LCMS 395 [M+1]; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.63 (s, 1H), 7.63 (d, J=3.5 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.92(d, J=8.5 Hz, 1H), 6.75-6.69 (m, 2H), 5.36 (d, J=3.8 Hz, 1H), 5.18-5.09(m, 2H), 4.64-4.54 (m, 2H), 4.02 (br. s., 1H), 3.83 (br. s., 2H), 2.99(br. s., 2H), 2.92-2.82 (m, 3H), 2.65 (s, 3H), 2.58 (br. s., 3H), 1.95(ddd, J=3.8, 9.5, 13.8 Hz, 1H)

Example 82 & 83 was made in a similar fashion from Example 79 & 78respectively

Example 82

381 [M + 1] (1S,2S,3S,5R)-3-[(2-methyl-2,3-dihydro-1H-isoindol-4-yl)oxy]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.62 (s, 1H), 7.56 (d, J = 3.8 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.89(dd, J = 7.8, 14.1 Hz, 2H), 6.77 (d, J = 3.8 Hz, 1H), 5.29 (q, J = 8.7Hz, 1H), 4.73 (ddd, J = 1.8, 3.5, 7.0 Hz, 1H), 4.65 (dd, J = 4.8, 8.8Hz, 1H), 4.18 (d, J = 4.5 Hz, 1H), 3.97 (d, J = 12.5 Hz, 4H), 3.00 (ddd,J = 7.0, 9.5, 14.6 Hz, 1H), 2.71 (s, 3H), 2.62 (s, 3H), 2.15-2.07 (m,1H) Example 83

395 [M + 1] (1S,2S,3S,5R)-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.62 (s, 1H), 7.57 (d, J = 3.8 Hz, 1H), 7.22 (t, J = 8.0Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.76 (d, J= 3.8 Hz, 1H), 5.23 (q, J = 8.9 Hz, 1H), 4.74-4.68 (m, 2H), 4.20 (d, J =5.5 Hz, 1H), 4.05 (s, 2H), 3.19-3.12 (m, 2H), 3.10-3.05 (m, 2H), 3.00(ddd, J = 7.0, 9.3, 14.3 Hz, 1H), 2.83 (s, 3H), 2.72 (s, 3H), 2.24-2.15(m, 1H)

Synthesis of tert-butyl6-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-1)

Step 1—Synthesis of 5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-one (EE-2)

To a solution of 5-fluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one (preparedin a similar manner as Bio. Med. Chem Letters, 20, 1004-1007, 2010) (1g, 6.02 mmol) and K₂CO₃ (2.5 g, 18 mmol) in dry DMF (10 mL) was addedMeI (1710 mg, 12.0 mmol) at 0° C. After the addition, the reaction wasstirred at 25° C. for 4 hours. The reaction mixture was partitionedbetween EtOAc and H₂O. The aqueous layer was extracted with EtOAc. Thecombined organic layers was washed with brine, dried over Na₂SO₄ andconcentrated to afford EE-2 (1 g, 92%) as a yellow solid. LCMS 181[M+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 6.73-6.69 (m, 1H), 6.51 (dd, J=2.0,11.3 Hz, 1H), 3.94 (s, 3H), 3.13-3.03 (m, 2H), 2.73-2.65 (m, 2H)

Step 2—Synthesis of 6-fluoro-8-methoxy-3,4-dihydroisoquinolin-1(2H)-one(EE-3)

To a solution of EE-2 (950 mg, 5.27 mmol) in 1,2-DCE/MeSO₃H (38 mL/29mL) at 0° C. was added portion-wise NaN₃ (1.4 mg, 21.1 mmol). Afteraddition, the mixture was stirred at 70° C. for 16 hrs. The mixture wascooled to 0° C., adjusted to pH 7-8 with addition of aqueous NaHCO₃(sat). The mixture was extracted with DCM (15 mL×2), dried over Na₂SO₄,filtered and concentrated to give EE-3 (1.15 g, 74%) as a brown solid.LCMS 196 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.70 (br. s., 1H), 6.85(dd, J=2.4, 11.9 Hz, 1H), 6.73 (dd, J=2.4, 8.9 Hz, 1H), 3.76 (s, 3H),3.21 (dt, J=3.5, 6.3 Hz, 2H), 2.80 (t, J=6.3 Hz, 2H)

Step 3—Synthesis of 6-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinoline(EE-4)

Compound EE-4 was prepared from EE-3 in a similar method as step 5 inScheme FF to give crude EE-4 (455 mg, >99%) as a yellow oil and useddirectly in the next step. LCMS 182 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δppm 6.63 (dd, J=2.3, 11.3 Hz, 1H), 6.48 (dd, J=2.3, 9.5 Hz, 1H), 3.75(s, 3H), 3.67-3.61 (m, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.61 (t, J=5.6 Hz,2H)

Step 4—Synthesis of 6-fluoro-1,2,3,4-tetrahydroisoquinolin-8-ol (EE-5)

Compound EE-5 was prepared from EE-4 in a similar method as step 6 inScheme FF to give crude EE-5 (228 mg, 54%) as a yellow solid. LCMS 168[M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.39-6.28 (m, 2H), 3.63 (s, 2H),2.85 (t, J=5.8 Hz, 2H), 2.63-2.57 (m, 2H)

Step 5—Synthesis of tert-butyl6-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-1)

Compound TP-1 was prepared from EE-5 in a similar method as step 7 inScheme FF to give TP-1 (182 mg, 50%) as a yellow solid. MS 212 [M-56+1];¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.11 (s, 1H), 6.45 (d, J=10.5 Hz, 2H),4.29 (s, 2H), 3.51 (m, J=5.8 Hz, 2H), 2.69 (m, J=5.6 Hz, 2H), 1.43 (s,9H)

Synthesis of tert-butyl5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-2)

Step 1—Synthesis of tert-butyl (pivaloyloxy)carbamate (FF-2)

To a solution of compound FF-1 (20 g, 150 mmol) in CHCl₃ (200 mL) wasslowly added pivalic anhydride (34 g, 180 mmol) in an ice bath and thenstirred at 70° C. for 16 h. The reaction solution was diluted with DCM(200 mL) and washed with saturated NaHCO₃ (200 mL×2) until pH-7. Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford a light yellow oil. The crude product wascrystallized with petroleum ether (20 mL) to afford FF-2 (18 g, 55%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.8 (br. s., 1H), 1.5 (s,9H), 1.3 (s, 9H)

Step 2—Synthesis of O-pivaloylhydroxylamine (FF-3)

To a solution of FF-2 (16 g, 70 mmol) in TBME (32 mL) was added CF₃SO₃H(10.6 g, 70.7 mmol) at 0° C. The reaction solution was stirred at 15° C.for 2 h. The reaction mixture was evaporated to give the crude productFF-3 (20 g, >99%) as a white solid and used directly in the nextreaction.

Step 3—Synthesis of 5-fluoro-2-methoxy-N-(pivaloyloxy)benzamide (FF-4)

To a solution of 5-fluoro-2-methoxybenzoic acid (4.50 g, 26.4 mmol) inTHF (90.0 mL) was added T3P (19 g, 29.1 mmol) at 0° C. After theaddition, the reaction mixture was stirred for 30 min at 25° C. To thereaction mixture was added DIPEA (13.8 mL, 8.82 mmol) followed by FF-3(7.28 g, 29.1 mmol). After the addition, the reaction mixture wasstirred at 25° C. for 16 hours. The reaction mixture was filtered andthe filtrate was partitioned between EtOAc and H₂O. The organic layerwas separated, dried over Na₂SO₄ and concentrated to afford the crudeproduct which was purified via flash column chromatography(EtOAc:petroleum ether=1˜100%, then MeOH:DCM=1%˜10%) to afford FF-4 (9g, >99%) as a white solid and used directly in the next reaction.

Step 4—Synthesis of 5-fluoro-8-methoxy-3,4-dihydroisoquinolin-1(2H)-one(FF-5)

A suspension of FF-4 (8.00 g, 28.0 mmol), KOAc (6.06 g, 61.7 mmol) and[Cp*RhCl₂]₂(867 mg, 1.40 mmol) in MeCN (100 mL) in a vessel was purgedwith N₂ for 5 min and then cooled to −40° C. with dry ice/acetone.Ethylene was purged into the vessel for 30 min then sealed and stirredat 25° C. for 16 h. The dark red suspension was filtered and thefiltrate cake was washed with CH₃CN. The combined filtrate wasconcentrated to afford the crude product which was purified via flashcolumn chromatography (EtOAc:Petroleum ether=1%-100%, thenMeOH:DCM=1−8%) to afford FF-5 (4.62 g, 84%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.85 (br. s., 1H), 7.32 (t, J=9.0 Hz, 1H), 6.99(dd, J=4.3, 9.3 Hz, 1H), 3.76 (s, 3H), 3.31-3.22 (m, 2H), 2.79 (t, J=6.3Hz, 2H)

Step 5—Synthesis of 5-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinoline(FF-6)

To a solution of FF-5 (4.66 g, 23.9 mmol) in dry THF (240 mL) was addedLiAIH4 (3.62 g, 95.5 mmol) portion-wise. After the addition, thereaction mixture was heated at 65° C. (reflux) for 2 hours. The reactionmixture was quenched with 4 mL of H₂O. The mixture was distilled inEtOAc and filtered. The filtrate cake was washed with EtOAc. Thefiltrate was dried over Na₂SO₄ and concentrated to afford the crudeproduct which was purified via flash column chromatography(MeOH:DCM=1˜8%) to afford FF-6 (2.9 g, 66%) as a yellow gum. ¹H NMR (400MHz, DMSO-d₆) δ ppm 6.92 (t, J=9.2 Hz, 1H), 6.73 (dd, J=4.4, 8.9 Hz,1H), 3.73 (s, 3H), 3.69 (s, 2H), 2.88 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.8Hz, 2H)

Step 6—Synthesis of 5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-ol (FF-7)

To a solution of FF-6 (2.86 g, 15.8 mmol) in DCM (28.6 mL) was addedBBr₃ (2.86 mL, 30.3 mmol) at −10° C. drop-wise. After the addition, thereaction mixture was stirred at 0° C. for 2 hours. The reaction mixturewas cooled to −10° C. and quenched with MeOH. The resulting mixture wasdiluted in H₂O, basified with sat. K₂CO₃ to pH 9˜10 and then extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to afford the crude productwhich was purified via flash column chromatography (MeOH:DCM=1:10) toafford FF-7 (1.0 g, 38%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 9.24 (br. s., 1H), 6.76 (t, J=9.0 Hz, 1H), 6.55 (dd, J=4.6, 8.7 Hz,1H), 3.69 (s, 2H), 2.90 (t, J=5.9 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H)

Step 7—Synthesis of tert-butyl5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-2)

To a solution of FF-7 (1.0 g, 6 mmol) in DCM (25.00 mL) and MeOH (5 mL)was added Boc₂O (1.4 g, 6.6 mmol) followed by Et₃N (2.08 mL, 15.0 mmol)at 0° C. After the addition, the reaction mixture was stirred at 25° C.for 16 hours. The reaction mixture was acidified with aq. citric acid topH 3-4 and the resulting mixture was partitioned between DCM and H₂O.The organic layer was separated and the aqueous layer was extracted withDCM. The combined organic layers were washed with sat. NaHCO₃, brine,dried over Na₂SO₄ and concentrated to afford the crude product which waspurified via flash column chromatography (MeOH:DCM=1:10) to afford theTP-2 (744 mg, 47%) as a white solid. MS 212 [M-55+1]; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.55 (s, 1H), 6.83 (t, J=9.0 Hz, 1H), 6.62 (dd, J=4.6,8.9 Hz, 1H), 4.32 (s, 2H), 3.52 (t, J=5.9 Hz, 2H), 2.63 (t, J=5.6 Hz,2H), 1.41 (s, 9H)

The procedures above in Scheme FF were used to synthesis thehydroxytetrahydroisoquinoline intermediates TP-3 through TP-7.

TP-3

228 LCMS = [M − 55 + 1] tert-butyl 6-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.13 (s, 1H), 6.68 (s, 2H), 4.29 (s, 2H), 3.53-3.45 (t, J = 5.6 Hz,2H), 2.74-2.64 (t, J = 5.5 Hz, 2H), 1.42 (s, 9H) TP-4

262 LCMS = [M − 55 + 1] tert-butyl 8-hydroxy-6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.36 (br. s., 1H), 7.00-6.96 (s, 1H), 6.95-6.91 (s, 1H), 4.40 (s, 2H),3.55 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 5.6 Hz, 2H), 1.44 (s, 9H) TP-5

208 LCMS = [M − 55 + 1] tert-butyl 8-hydroxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, CDCl₃) δ ppm6.58-6.51 (m, 1H), 6.46 (s, 1H), 4.51 (br. s., 2H), 3.64- 3.60 (m, 2H),2.80-2.76 (m, 2H), 2.25 (s, 3H), 1.51 (s, 9H) TP-6

230 LCMS = [M − 55 + 1] tert-butyl 5,6-difluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.04 (s, 1H), 6.63 (dd, J = 6.8, 12.3 Hz, 1H), 4.30 (s, 2H), 3.60-3.50(t, J = 5.8 Hz, 2H), 2.75-2.65 (t, J = 5.9 Hz, 2H), 1.42 (s, 9H) TP-7

320 LCMS = [M − 55 + 1] tert-butyl 8-hydroxy-5-iodo-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.93 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 4.32(s, 2H), 3.59-3.49 (m, 2H), 2.57 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H)

Synthesis of tert-butyl8-hydroxy-6-(2-hydroxypropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-9)

Step 1: Synthesis of benzyl 2-(benzyloxy)-4-bromobenzoate (GG-2)

To a solution of the salicyclic acid GG-1 (50 g, 230 mmol) in THF (1000mL) was added potassium carbonate (95.5 g, 691 mmol), tetrabutylammonium bromide (14.9 g, 46.1 mmol) and benzyl bromide (95.8 g, 576mmol). The reaction was stirred at 20° C. for 16 hours. The solution wasfiltered and concentrated under vacuum to afford the desired productGG-2 as a crude brown solid (150 g). This material was used in the nextstep without further purification. TLC (PE./EA=10:1, Rf˜0.5)

Step 2: Synthesis of 2-(benzyloxy)-4-bromobenzoic acid (GG-3)

To a solution of GG-2 (140 g, 352 mmol, crude, ˜53% of purity) inMeOH/water/DCM (500 mL/500 mL/500 mL) was added lithium hydroxide (44.4g, 1060 mmol) at 10° C. The reaction was stirred at 70° C. for 16 hours.The solution was concentrated under vacuum and a yellow solidprecipitated from the solution. The solids were filtered and the filtercake was washed with water (50 mL×2). The yellow solid was acidifiedwith 1N HCl to pH=2. Yellow solid was filtered and dried in an infraredoven to give compound GG-3 (43.3 g, 40%) as a yellow solid. ¹NMR (400MHz, DMSO-d6) δ ppm 12.76 (bs, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52-7.47(m, 2H), 7.44 (d, J=1.8 Hz, 1H), 7.43-7.38 (m, 2H), 7.37-7.31 (m, 1H),7.23 (dd, J=1.8, 8.3 Hz, 1H), 5.25 (s, 2H).

Step 3: Synthesis of 2-(benzyloxy)-4-bromo-N-(pivaloyloxy)-benzamide(GG-4)

To a solution of GG-3 (31.2 g, 101.58 mmol) in THF (630 mL) was addedT₃P (71.1 g, 112 mmol) at 0° C. After the addition, the reaction mixturewas stirred for 30 minutes at 25° C. To the above solution was addedDIPEA (78.8 g, 609 mmol) followed by O-pivaloylhydroxylamine (28 g, 112mmol). After the addition, the reaction mixture was stirred at 25° C.for 2 hours. The solution was transferred to a separatory funnel withEtOAc (500 mL) and washed with 1 portion water (300 mL), 1 portioncitric acid aq. (300 mL), 1 portion sat. NaHCO₃, and 1 portion brine(300 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated under vacuum. The crude residue was purified via flashcolumn chromatography (silica gel, petroleum ether:EtOAc=7:1) to affordcompound GG-4 (30.4 g, 74%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6)δ ppm 10.74 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.52-7.35 (m, 5H), 7.28 (d,J=1.5 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.23 (d, J=1.5 Hz, 1H), 5.27 (s,2H), 1.34 (s, 9H)

Step 4: Synthesis of8-(benzyloxy)-6-bromo-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl pivalate(GG-5)

A suspension of GG-4 (40.7 g, 100.18 mmol), KOAc (10.8 g, 110 mmol) andCp₂RhCl₂ (3.1 g, 5.01 mmol) in MeCN (1300 mL) was cooled to 0° C. andthe solution was sparged with ethylene gas for 45 minutes. The vesselwas sealed and stirred at 10° C. for 16 hours. The reaction suspensionwas filtered and the cake was washed with 2 portions of a 5:1 mixture ofDCM/MeOH (100 mL). The filtrate was concentrated under reduced pressureto give the crude product (50 g) as a yellow solid. The crude residuewas purified via flash column chromatography (silica gel, DCM:MeOH=40:1)to afford compound GG-5 (28 g, 84%) as a yellow solid. LCMS [M+H+Na] 356observed; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.79 (t, J=3.1 Hz, 1H)7.53-7.59 (m, 2H) 7.35-7.42 (m, 2H) 7.30-7.34 (m, 1H) 7.26 (d, J=2.0 Hz,1H) 7.15 (d, J=2.0 Hz, 1H) 5.20 (s, 2H) 3.25 (td, J=6.1, 3.6 Hz, 2H)2.83 (t, J=6.3 Hz, 2H).

Step 5: Synthesis of8-(benzyloxy)-6-bromo-3,4-dihydroisoquinolin-1(2H)-one (GG-6)

To a mixture of GG-5 (36.5 g, 110 mmol) in anhydrous THF (700 mL) wasadded BH₃.Me₂S (10M, 33 mL, 330 mmol) at 0° C. dropwise under N₂. Afterthe addition, the reaction was stirred at 5° C. for 12 hours. At thisstage, the reaction mixture was heated at 78° C. (reflux) for 3 hours todrive completion. The reaction was allowed to cool gradually to rt andcarefully quenched with 70 mL of MeOH at 0° C. The solution wasconcentrated then taken up in THF (2 mL) and MeOH (10 mL) andtransferred to a microwave vial. The solution was heated at 120° C. in amicrowave reactor for 1 hour. The solution was concentrated to afford ablack solid. The crude residue was purified via flash columnchromatography (120 g silica gel x 3, MeOH/DCM=10%-20%) to affordcompound GG-6 (8.28 g, 24%) as a brown solid. LCMS [M+H] 319 observed;¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.99 (br. s, 1H) 7.37-7.50 (m, 5H) 7.23(d, J=1.3 Hz, 1H) 7.11 (d, J=1.3 Hz, 1H) 5.21 (s, 2H) 4.11 (s, 2H) 2.97(t, J=5.9 Hz, 2H).

Step 6: Synthesis of tert-butyl8-(benzyloxy)-6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (GG-7)

To a mixture of GG-6 (10.99 g, 34.537 mmol) in DCM (110 mL) and THF (22mL) were added Et₃N (10.5 g, 104 mmol) and (Boc)₂O (11.3 g, 51.8 mmol)at 10° C. The reaction was stirred at 10° C. for 16 hours. The mixturewas concentrated under vacuum to give the crude product as black gum.The crude residue was purified by flash column chromatography (120 g ofsilica gel, EtOAc/Petroleum ether from 4% to 7%) to afford compound GG-7(9.9 g, 68.5%) as yellow gum. LCMS [M+H-Boc] 319 observed; ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.48-7.30 (m, 5H), 6.98-6.88 (m, 2H), 5.15-4.96(m, 2H), 4.60-4.44 (m, 2H), 3.71-3.54 (m, 2H), 2.88-2.71 (m, 2H), 1.50(s, 9H).

Step 7: Synthesis of 2-(tert-butyl) 6-methyl8-(benzyloxy)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate (GG-8)

A mixture of GG-7 (600 mg, 1.43 mmol), DPPP (296 mg, 0.717 mmol), TEA(435 mg, 4.30 mmol) and Pd(OAc)₂ (161 mg, 0.717 mmol) in MeOH (20 mL)and DMF (20 mL) was heated at 120° C. under 22 bar of carbon monoxidefor 24 hours. The mixture was concentrated under vacuum and transferredto a separatory funnel with EtOAc. The solution was washed with 5portions brine, dried over sodium sulfate, filtered, and concentratedunder vacuum. The crude residue was purified via flash columnchromatography (12 g, silica gel, 20% EtOAc/petroleum ether) to affordcompound GG-8 (440 mg, 77% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.54-7.28 (m, 7H), 5.22-5.08 (m, 2H), 4.67-4.54 (m,2H), 3.91 (s, 3H), 3.70-3.57 (m, 2H), 2.93-2.77 (m, 2H), 1.50 (s, 9H).

Step 8: Synthesis of tert-butyl8-(benzyloxy)-6-(2-hydroxypropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(GG-9)

To a colorless solution of GG-8 (327 mg, 0.823 mmol) in dry THF (15 mL)was added MeMgBr (3.0 M solution in diethyl ether, 1.65 mL, 4.94 mmol)dropwise at 0° C. The mixture was stirred at 17° C. for 1.5 hours. Thesolution was cooled to 0° C. and quenched with water (10 mL). Thesolution was transferred to a separatory funnel with EtOAc and thephases were separated. The aqueous phase was extracted with 2 portionsEtOAc (20 mL). the combined organic extracts were washed with 1 portionbrine (30 mL), dried over sodium sulfate, filtered, and concentratedunder vacuum. The crude residue was purified via flash columnchromatography (silica gel, 12 g, petroleum ether:EA=3:1) to affordcompound GG-9 (320 mg, 98%) as colorless gum. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.29-7.49 (m, 5H) 6.97 (s, 1H) 6.84 (s, 1H) 5.12(br. s., 2H) 4.58 (s, 2H) 3.65 (br. s., 2H) 2.82 (br. s., 2H) 1.57 (s,6H) 1.49 (s, 9H).

Step 9: Synthesis of tert-butyl8-hydroxy-6-(2-hydroxypropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-9)

A mixture of GG-9 (290 mg, 0.73 mmol) and Pd/C (105 mg) in MeOH (10 mL)was stirred at 15° C. for 5 hours under a balloon of hydrogen. Themixture was filtered through a pad of Celite and the filtrateconcentrated under vacuum. The crude residue was purified via flashcolumn chromatography (4 g, silica gel, 60% EtOAc/petroleum ether) toafford compound TP-9 (144 mg, 64%) as a white solid. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 6.91 (br. s., 1H), 6.76 (s, 1H), 4.53 (br. s., 2H),3.63 (br. s., 2H), 2.80 (br. s., 2H), 1.55 (s, 6H), 1.50 (s, 9H).

A sequence consisting of Steps 1-6 & 9 from Scheme GG were used tosynthesis the hydroxytetrahydroisoquinoline intermediates TP-8 (SchemeIII), TP-10-12 from the appropriate salicyclic acid.

226 LCMS = [M − 55 + 1] tert-butyl 5-fluoro-8-hydroxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, MeOD) δ ppm 6.45(d, J = 6.3 Hz, 1H), 4.40 (s, 2H), 3.66-3.50 (m, 2H), 2.70 (t, J = 5.9Hz, 2H), 2.14 (d, J = 1.5 Hz, 3H), 1.50-1.47 (m, 9H)

246 LCMS = [M − 55 + 1] tert-butyl 6-chloro-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.06 (s, 1H), 6.76 (d, J = 6.3 Hz, 1H), 4.31 (s, 2H), 3.54 (t, J = 5.8Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H)

tert-butyl 6-bromo-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.04 (s, 1H), 6.88 (d, J = 5.8 Hz, 1H), 4.30 (s, 2H), 3.54 (t, J = 5.8Hz, 2H), 2.69 (t, J = 5.9 Hz, 2H), 1.42 (s, 9H)

272 LCMS = [M − 55 + 1] tert-butyl 6-bromo-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate; ¹H NMR (400 MHz, CDCl₃) δ ppm6.94-6.66 (m, 2H), 4.46 (m, 2H), 3.61 (t, J = 5.6 Hz, 2H), 2.76 (m, 2H),1.51 (s, 9H)

Synthesis of tert-butyl6-ethyl-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-13)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-6-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (HH-1)

A mixture of GG-7 (530 mg, 1.27 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (410 mg, 2.67 mmol),K₃PO₄.3H₂O (675 mg, 2.53 mmol), PdCl₂(dppf) (93 mg, 0.013 mmol) indioxane (20 mL) and H₂O (5 mL) was degassed with N₂ heated at 100° C.for 2 hours. The mixture was purified by pre-TLC (PetroleumEther/EtOAc=8/1) to afford HH-1 (370 mg, 80%) as a colorless gum. LCMS266 [M-Boc+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.51-7.28 (m, 5H), 6.83 (d,J=12.0 Hz, 2H), 6.65 (dd, J=10.9, 17.4 Hz, 1H), 5.69 (d, J=17.6 Hz, 1H),5.22 (d, J=10.8 Hz, 1H), 5.12 (br. s., 2H), 4.58 (br. s., 2H), 3.73-3.56(m, 2H), 2.90-2.73 (m, 2H), 1.50 (s, 9H)

Step 2—Synthesis of tert-butyl6-ethyl-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-13)

A mixture of HH-1 (370 mg, 1.01 mmol) and Pd/C (370 mg) in MeOH (20 mL)was degassed with H₂ and stirred at 50° C. under H₂ (50 psi) for 24 hrs.The mixture was filtered and the filtrate was concentrated in vacuo toafford crude material which was purified by silica gel chromatographyeluted with EtOAc in petroleum ether from 0 to 20% to afford TP-12 (210mg, 75%) as a white solid. LCMS 222 [M-55+1]; ¹H NMR (400 MHz, CDCl₃) δppm 6.57 (br. s., 1H), 6.48 (s, 1H), 4.51 (br. s., 2H), 3.63 (br. s.,2H), 2.78 (br. s, 2H), 2.62-2.45 (q, J=7.5 Hz, 2H), 1.50 (s, 9H), 1.20(t, J=7.5 Hz, 3H)

Synthesis of tert-butyl6-(difluoromethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-14)

Step 1: Synthesis of tert-butyl8-(benzyloxy)-6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (II-1)

GG-7 (1000 mg, 2.390 mmol) in an oven dried two necked flask equippedwith a thermometer was dissolved in tetrahydrofuran (22.0 mL, c=0.109M), cooled to −78° C., tert-butyllithium (459 mg, 7.17 mmol, 4.22 mL,1.7 M) was added slowly under N₂ while maintaining the internaltemperature around −70° C., stirred at −78° C. for 30 min, N,N-dimethylformamide (262 mg, 3.59 mmol) was added dropwise and stirred at −78° C.for 1.5 h. The reaction was quenched by std. NH₄Cl at −78° C., extractedwith EtOAc 3 times. The organic layers were combined, washed with brine,dried over Na₂SO₄, concentrated and purified by column chromatographywith 15% EtOAc/heptane to give II-1 (300 mg, 34% yield) as a colorlessoil.

LCMS [M+1-Boc] 268.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.91 (t, J=5.38 Hz, 2H) 3.68 (t, J=5.69 Hz, 2H) 4.65 (s, 2H) 5.17 (br.s., 2H) 7.29 (d, J=9.05 Hz, 2H) 7.31-7.37 (m, 1H) 7.40 (t, J=7.27 Hz,2H) 7.43-7.48 (m, 2H) 9.92 (s, 1H)

Step 2: Synthesis of tert-butyl8-(benzyloxy)-6-(difluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(II-2)

To a solution of II-1 (300 mg, 0.816 mmol) in DCM (16.3 mL, c=0.05 M) at0° C. was added (diethylamino)sulfur trifluoride (1320 mg, 8.16 mmol,1070 uL). The reaction was removed from the ice bath and stirred at r.t.overnight. The reaction was diluted with DCM and quenched with std.NaHCO₃, stirred at r.t. until CO₂ evolution ceased. The layers wereseparated and the aqueous was extracted with DCM. The organic layer wasdried over Na₂SO₄ and concentrated, purified by column chromatographywith 15% EtOAc/heptane to give II-2 (240 mg, 75% yield) as a clear oil.

LCMS [M+1-Boc] 290.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.86 (t, J=5.26 Hz, 2H) 3.66 (t, J=5.62 Hz, 2H) 4.61 (s, 2H) 5.13 (br.s., 2H) 6.58 (t, J=57.22 Hz, 1H) 6.92 (d, J=8.31 Hz, 2H) 7.31-7.48 (m,5H)

Step 3: Synthesis of tert-butyl6-(difluoromethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-14)

To a solution of II-2 (240 mg, 0616 mmol) in methanol (10 mL) was addedpalladium on carbon (66 mg, 0.616 mmol). The reaction solution wasdegassed and back filled with hydrogen gas. The mixture was fitted witha hydrogen balloon and stirred at rt overnight. The reaction wasfiltered, the solvents removed in vacuo and the material purified bycolumn chromatography with 20% EtOAc/heptane to give TP-14 (175 mg, 95%yield) as a white solid.

LCMS [M+1-tBu] 242. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9H)2.84 (br. s., 2H) 3.66 (t, J=5.81 Hz, 2H) 4.56 (br. s., 2H) 6.53 (t,J=57.22 Hz, 1H) 6.76 (s, 1H) 6.84 (br. s., 1H)

Synthesis of tert-butyl6-(1,1-difluoroethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-15)

Step 1: Synthesis of benzyl 4-acetyl-2-(benzyloxy)benzoate (JJ-1)

The mixture of GG-2 (8544 mg, 21.51 mmol), tributyl(1-ethoxyvinyl)tin(8160 mg, 22.6 mmol), Pd₂(dba)₃ (394 mg, 0.430 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (536 mg, 0.860 mmol) intoluene (108 mL, c=0.2 M) was degassed and heated at 90° C. for 18 h.Toluene was removed and the crude was carried to next step.

The crude was dissolved in THF (108 mL, c=0.20 M), hydrochloric acid(6670 mg, 183 mmol, 45.7 mL, 4.0 M) was added, stirred at r.t. for 2hrs. The organic solvent was removed; H₂O was added, extracted withEtOAc 3 times. The organic layers were combined, washed with brined,dried over Na₂SO₄, filtered and concentrated, purified with silica gelchromatography eluted with 15% EtOAc/heptane to give 7180 mg yellow oil.

LCMS [M+1] 361.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.60 (s, 3H)5.23 (s, 2H) 5.37 (s, 2H) 7.29-7.42 (m, 8H) 7.45 (d, J=6.85 Hz, 2H) 7.54(dd, J=8.01, 1.28 Hz, 1H) 7.62-7.65 (m, 1H) 7.90 (d, J=7.95 Hz, 1H)

Step 2: Synthesis of benzyl 2-(benzyloxy)-4-(1,1-difluoroethyl)benzoate(JJ-2)

JJ-1 (7.380 g, 20.48 mmol) was added deoxofluor (22.7 g, 102 mmol). Thereaction mixture was heated to 80° C. for 4.5 hrs, cooled to r.t.,poured into std. NaHCO₃, and after CO₂ evolution ceased, the aqueous wasextracted with EtOAc 3 times. The organic layer was concentrated undervacuum, purified by column chromatography with 10% EtOAc/heptane to giveJJ-2 (5.94 g, 76% yield) as a colorless oil which solidified uponvacuum.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.89 (t, J=18.16 Hz, 3H) 5.19 (s,2H) 5.36 (s, 2H) 7.12 (d, J=8.07 Hz, 1H) 7.17 (s, 1H) 7.29-7.42 (m, 8H)7.45 (d, J=6.72 Hz, 2H) 7.89 (d, J=8.07 Hz, 1H)

Step 3: Synthesis of 2-(benzyloxy)-4-(1,1-difluoroethyl)benzoic acid(JJ-3)

Following a similar procedure as step 2 in Scheme GG, JJ-2 washydrolyzed to JJ-3 (4.49 g, 99%) as white solid.

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (t, J=18.89 Hz, 3H) 5.26 (s, 2H)7.19 (d, J=7.95 Hz, 1H) 7.29-7.36 (m, 2H) 7.40 (t, J=7.34 Hz, 2H) 7.51(d, J=7.21 Hz, 2H) 7.71 (d, J=7.95 Hz, 1H) 12.89 (br. s., 1H)

Step 4-8: Synthesis of tert-butyl6-(1,1-difluoroethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-15)

Following similar procedures as step 3 in Scheme GG (1.30 g, 70%), step4 in Scheme GG (684 mg, 65%), steps 5 in Scheme FF and step 6 in SchemeGG (575 mg, 77%), step 9 in Scheme GG (400 mg, 90%), JJ-3 was convertedto TP-15.

LCMS [M+1-Boc] 214.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9H)1.87 (t, J=18.10 Hz, 3H) 2.83 (br. s., 2H) 3.65 (t, J=5.69 Hz, 2H) 4.56(br. s., 2H) 6.76 (s, 1H) 6.83 (br. s., 1H)

Synthesis of tert-butyl8-hydroxy-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (TP-16)

Step 1-3: Synthesis of 8-methoxy-1,2,3,4-tetrahydro-2,6-naphthyridine(KK-4)

Following similar procedures as step 3 in Scheme GG (939 mg, 57%), step4 in Scheme GG using cesium pivolate and dichloroethane in place ofpotassium acetate and acetonitrile (290 mg, 70%), and steps 5 in SchemeFF (136 mg, 50%), KK-1 was converted to KK-4.

LCMS [M+1] 165.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.77 (t, J=5.81Hz, 2H) 3.11 (t, J=5.81 Hz, 2H) 3.90 (s, 3H) 3.94 (s, 2H) 8.03 (d,J=2.93 Hz, 2H)

Step 4: Synthesis of 5,6,7,8-tetrahydro-2,6-naphthyridin-4-ol (KK-5)

KK-4 (136.0 mg, 0.828 mmol) in 5 mL 48% HBr and 3 mL glacial acetic acidwas sealed and refluxed at 120° C. for 4 days. The reaction was cooledto RT, concentrated off the acetic acid by azeotroping from heptanes 3times, neutralized by careful addition of 5 N NaOH until pH around 9.Rotavaporated to remove most H₂O, added MeOH, dried packed with silicagel. The product was purified by column chromatography with 10% MeOH/DCMwith 0.5% NH₄OH to give KK-5 (124 mg, 100%). LCMS [M+1] 151.10.

Step 5: Synthesis of tert-butyl8-hydroxy-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (TP-16)

Following similar procedures as step 6 in Scheme GG, KK-5 was convertedto TP-16 (106 mg, 51%).

LCMS [M-55+1] 228. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.13 (s, 1H), 6.68(s, 2H), 4.29 (s, 2H), 3.53-3.45 (t, J=5.6 Hz, 2H), 2.74-2.64 (t, J=5.5Hz, 2H), 1.42 (s, 9H)

Synthesis of tert-butyl8-hydroxy-5-methyl-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate(TP-17)

Step 1: Synthesis of(5-(benzyloxy)-2-methylpyridin-4-yl)(ethoxy)methanol (LL-2)

Ethyl 5-hydroxy-2-methylisonicotinate (LL-1) (synthesis described inWO10100475) (2190 mg, 17.22 mmol) and N-benzyl bromide (3540 mg, 20.7mmol), K₂CO₃ (4810 mg, 34.4 mmol) in 20 mL DMF was heated at 80° C.overnight. After the reaction mixture cooled to r.t., EtOAc was added,washed with H₂O 3 times. The organic layer was concentrated, purified bycolumn chromatography with 30% EtOAc/heptane to give LL-2 (16 g, 48%yield) as a brown solid.

LCMS [M+1] 272.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=7.15Hz, 3H) 2.54 (s, 3H) 4.39 (q, J=7.13 Hz, 2H) 5.23 (s, 2H) 7.34 (d,J=7.09 Hz, 1H) 7.36-7.43 (m, 2H) 7.44-7.51 (m, 3H) 8.35 (s, 1H)

Step 2: Synthesis of (5-(benzyloxy)-2-methylpyridin-4-yl)methanediol(LL-3)

To a solution of LL-2 (2160 mg, 7.961 mmol) in 20 mL MeOH was addedsodium hydroxide (1590 mg, 39.8 mmol, 7.96 mL, 5.0 M), and the reactionwas heated at 50° C. for 4 hrs. The mixture was cooled to r.t., MeOH wasevaporated, H₂O was added, neutralized with 1 N HCl to pH about 4, theyellow solid crashed out which was filtered and rinsed with H₂O to giveLL-3 (1.66 g, 86% yield).

LCMS [M+1] 244.10. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H) 5.27 (s,2H) 7.33 (d, J=7.21 Hz, 1H) 7.35-7.43 (m, 3H) 7.44-7.52 (m, 2H) 8.41 (s,1H)

Step 3-7: —Synthesis of tert-butyl8-hydroxy-5-methyl-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate(TP-17)

Following similar procedures as step 3 in Scheme GG (1.60 g, 68%), step4 in Scheme GG using cesium pivolate and dichloroethane in place ofpotassium acetate and acetonitrile (620 mg, 49%), steps 5 in Scheme FF(366 mg, 64%), step 6 in Scheme GG (483 mg, 96%), and step 9 in SchemeGG (386 mg, 100%), LL-3 was converted to TP-17.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H) 2.41 (s, 3H) 2.71 (t,J=5.38 Hz, 2H) 3.69 (t, J=5.75 Hz, 2H) 4.59 (s, 2H) 7.95 (s, 1H)

Synthesis of tert-butyl6-cyano-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-18)

Step 1: Synthesis of tert-butyl8-(benzyloxy)-6-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate (MM-1)

Compound GG-7 (700 mg, 1.67 mmol) was dissolved in DMF (5.00 mL).Zn(CN)₂ (236 mg, 2.01 mmol) was added to the above solution. Thereaction solution was degassed for 2 min. Pd(PPh₃)₄(580 mg, 0.502 mmol)was added to the above mixture. The reaction mixture was degassed withN₂ for 3 min. Then the reaction mixture was heated by microwave at 150°C. for 30 min. The reaction solution became black from yellow. Thereaction solution was cooled and diluted with EtOAc/H₂O (8 mL/8 mL),then the mixture was filtered, and the filtrate was extracted. Theorganic layer was separated, dried and evaporated to give the crudeproduct which was purified by flash chromatography with petroleumether/EtOAc from 0-25% to give MM-1 (350 mg, 57%) as a white solid. LCMS265 [M-Boc]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.52-7.32 (m, 6H), 7.29(s, 1H), 5.22 (br. s., 2H), 4.53-4.40 (m, 2H), 3.54 (t, J=5.6 Hz, 2H),2.79 (t, J=5.5 Hz, 2H), 1.41 (s, 9H)

Step 2: Synthesis of tert-butyl6-cyano-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-18)

Compound MM-1 (320 mg, 0.878 mmol) was dissolved in MeOH (3 mL). Pd/C(93 mg, 0.44 mmol) was added to the reaction solution and degassed by H₂balloon three times, and stirred under H₂ balloon at 20° C. for 1 hour.DCM (5 mL) was added to the above mixture, the reaction mixture wasfiltered and concentrated to give the crude product, which was purifiedby flash chromatography with petroleum ether/EtOAc from 0-50% to giveTP-18 as a white solid (125 mg, 51.9%). LCMS [219-tBu]+; ¹H NMR (400MHz, CDCl₃) δ ppm 7.45-7.28 (m, 1H), 7.10-6.95 (m, 1H), 6.87 (br. s.,1H), 4.57 (br. s., 2H), 3.66 (t, J=5.9 Hz, 2H), 2.82 (br. s., 2H), 1.53(s, 9H)

Examples 84-98 were made in a similar fashion to Example 78 in Scheme CCusing the appropriate NBoc-protected tetrahydroisoquinoline in step 1.

399 [M + 1] (1S,2S,3S,5R)-3-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.63 (s, 1H), 7.62 (d, J = 3.5 Hz, 1H), 6.96-6.89 (m,1H), 6.86-6.80 (m, 1H), 6.72 (d, J = 3.5 Hz, 1H), 5.31 (d, J = 3.8 Hz,1H), 5.16-5.06 (m, 2H), 4.59- 4.49 (m, 2H), 4.00-3.95 (m, 1H), 3.82 (s,2H), 2.91 (t, J = 5.8 Hz, 2H), 2.88-2.77 (m, 1H), 2.64 (s, 3H), 2.57 (t,J = 5.8 Hz, 2H), 1.92 (ddd, J = 3.8, 9.3, 13.6 Hz, 1H)

399 [M + 1] (1S,2S,3S,5R)-3-((6-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.61 (s, 1H), 7.55 (d, J = 3.5 Hz, 1H), 6.75 (d, J = 3.8Hz, 1H), 6.68 (dd, J = 2.3, 10.8 Hz, 1H), 6.49 (dd, J = 2.1, 9.2 Hz,1H), 5.24 (q, J = 8.8 Hz, 1H), 4.74- 4.63 (m, 2H), 4.17 (d, J = 4.8 Hz,1H), 3.93 (s, 2H), 3.06 (t, J = 5.9 Hz, 2H), 3.03-2.94 (m, 1H), 2.80 (t,J = 5.8 Hz, 2H), 2.22-2.10 (m, 1H)

415 [M + 1] (1S,2S,3S,5R)-3-((5-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.64 (s, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.25 (d, J = 9.0Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 3.5 Hz, 1H), 5.25 (q, J= 9.0 Hz, 1H), 4.72 (dd, J = 4.8, 8.3 Hz, 2H), 4.20 (d, J = 4.5 Hz, 1H),4.03 (s, 2H), 3.16 (t, J = 6.0 Hz, 2H), 3.07-2.91 (m, 1H), 2.83 (t, J =5.8 Hz, 2H), 2.74 (s, 3H), 2.27-2.05 (m, 1H)

415 [M + 1] (1S,2S,3S,5R)-3-((6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.62 (s, 1H), 7.62 (d, J = 3.8 Hz, 1H), 6.92 (s, 1H),6.76 (s, 1H), 6.72 (d, J = 3.5 Hz, 1H), 5.41-5.35 (m, 1H), 5.10 (d, J =9.3 Hz, 2H), 4.63-4.44 (m, 2H), 3.99- 3.91 (m, 1H), 3.78 (s, 2H),2.93-2.78 (m, 3H), 2.69-2.59 (m, 4H), 2.02-1.88 (m, 1H)

395 [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2;3-d]pyrimidin-7-yl)-5-[(6-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]cyclopentane-1,2- diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.64 (s, 1H), 7.56 (d, J = 3.8 Hz, 1H), 6.77 (d, J = 3.8Hz, 1H), 6.70-6.66 (s, 1H), 6.61-6.55 (s, 1H), 5.34- 5.23 (m, 1H),4.73-4.66 (m, 2H), 4.22-4.16 (m, 1H), 3.96 (s, 2H), 3.07-3.06 (m, 3H),2.84- 2.76 (m, 1H), 2.73 (s, 3H), 2.30 (s, 3H), 2.18- 2.07 (m, 1H)

459 [M + 1] (1S,2S,3S,5R)-3-((6-bromo-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.63 (s, 1H), 7.57 (d, J = 3.5 Hz, 1H), 7.13 (s, 1H),7.05- 6.94 (m, 1H), 6.76 (d, J = 3.8 Hz, 1H), 5.22 (q, J = 9.0 Hz, 1H),4.76-4.67 (m, 2H), 4.24-4.14 (m, 1H), 4.09 (s, 2H), 3.23 (t, J = 6.0 Hz,2H), 3.00 (ddd, J = 7.3, 9.3, 14.3 Hz, 1H), 2.95-2.86 (m, 2H), 2.73 (s,3H), 2.32-2.15 (m, 1H)

449 [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2- diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.62 (s, 1H), 7.57 (d, J = 3.5 Hz, 1H), 7.13 (s, 1H),7.07 (s, 1H), 6.75 (d, J = 3.8 Hz, 1H), 5.23 (q, J = 9.0 Hz, 1H), 4.76(dd, J = 2.6, 4.6 Hz, 1H), 4.72 (dd, J = 4.9, 8.9 Hz, 1H), 4.18 (d, J =5.0 Hz, 1H), 4.03 (s, 2H), 3.12-3.06 (m, 2H), 3.00 (ddd, J = 7.3, 9.3,14.3 Hz, 1H), 2.88 (t, J = 5.6 Hz, 2H), 2.71 (s, 3H), 2.27-2.17 (m, 1H)

428 [M + 23] 8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile ¹H NMR (400 MHz, MeOD-d₄)δ ppm 8.64 (s, 1H), 7.58 (d, J = 3.5 Hz, 1H), 7.24 (s, 1H), 7.17 (s,1H), 6.77 (d, J = 3.8 Hz, 1H), 5.29-5.19 (m, 1H), 4.80-4.69 (m, 2H),4.19 (d, J = 4.5 Hz, 1H), 4.03 (s, 2H), 3.10-3.07 (m, 2H), 3.05-2.97 (m,1H), 2.90-2.84 (m, 2H), 2.74 (s, 3H), 2.27-2.23 (m, 1H)

417 [M + 1] (1S,2S,3S,5R)-3-((5,6-difluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.62 (s, 1H), 7.55 (d, J = 3.8 Hz, 1H), 7.02 (dd, J =6.9, 12.2 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 5.21-5.11 (m, 1H),4.76-4.70 (m, 1H), 4.70-4.63 (m, 1H), 4.22-4.15 (m, 3H), 3.37 (t, J =6.3 Hz, 2H), 3.03- 2.90 (m, 3H), 2.72 (s, 3H), 2.31-2.21 (m, 1H)

433 [M + 1] (1S,2S,3S,5R)-3-((6-chloro-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.63 (s, 1H), 7.63 (d, J = 3.5 Hz, 1H), 7.14 (d, J = 6.3Hz, 1H), 6.72 (d, J = 3.8 Hz, 1H), 5.41 (d, J = 3.0 Hz, 1H), 5.21-4.96(m, 2H), 4.65-4.46 (m, 2H), 4.06-3.90 (m, 3H), 3.08 (t, J = 5.8 Hz, 2H),2.91- 2.78 (m, 1H), 2.77-2.69 (m, 2H), 2.64 (s, 3H), 2.04-1.90 (m, 1H)

477 [M + 1] (1S,2S,3S,5R)-3-((6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.63 (s, 1H), 7.63 (d, J = 3.76 Hz, 1H), 7.22 (d, J =5.52 Hz, 1H), 6.72 (s, 1H), 5.40 (d, J = 3.76 Hz, 1H), 5.01- 5.17 (m,2H), 4.51-4.62 (m, 2H), 3.88-4.01 (m, 3H), 3.06 (t, J = 5.90 Hz, 2H),2.78-2.87 (m, 1H), 2.71 (t, J = 5.27 Hz, 2H), 2.64 (s, 3H), 2.00-1.95(m, 1H)

382.1 [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δppm 8.63 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.64 (d, J = 3.8 Hz, 1H),6.72 (d, J = 3.5 Hz, 1H), 5.43 (d, J = 4.3 Hz, 1H), 5.17-5.06 (m, 2H),4.71 (br. s., 1H), 4.62- 4.53 (m, 1H), 4.04-3.97 (m, 3H), 3.10 (br. s.,2H), 2.95-2.83 (m, 1H), 2.78 (br. s., 2H), 2.64 (s, 3H), 2.08-1.94 (m,1H)

396.1 [M + 1] (1S,2S,3S,5R)-3-((1-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.62 (s, 1H), 8.03 (s, 1H), 7.56 (d, J = 3.8 Hz, 1H),6.75 (d, J = 3.5 Hz, 1H), 5.29-5.12 (m, 1H), 4.75 (ddd, J = 4.8, 9.0,13.6 Hz, 2H), 4.20 (d, J = 4.3 Hz, 1H), 4.09 (s, 2H), 3.22 (t, J = 6.0Hz, 2H), 3.05-2.94 (m, 1H), 2.79 (t, J = 5.8 Hz, 2H), 2.72 (s, 3H), 2.40(s, 3H), 2.30-2.19 (m, 1H)

439 ob- served [M + H] (1S,2S,3S,5R)-3-((6-(2-hydroxypropan-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 8.64 (s, 1 H) 7.57 (d, J = 3.5 Hz, 1 H)7.00 (s, 1 H) 6.88 (s, 1 H) 6.77 (d, J = 3.5 Hz, 1 H) 5.29 (q, J = 8.8Hz, 1 H) 4.73 (s, 2 H) 4.22 (d, J = 4.8 Hz, 1 H) 4.02 (s, 2 H) 3.12 (t,J = 5.9 Hz, 2 H) 3.03 (ddd, J = 14.6, 9.5, 7.0 Hz, 1 H) 2.87 (t, J = 5.8Hz, 2 H) 2.73 (s, 3 H) 2.17 (ddd, J = 14.3, 8.4, 3.6 Hz, 1 H) 1.53 (s, 8H)

507 M + 1 (1S,2S,3S,5R)-3-((5-iodo-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.64 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H),6.80 (d, J = 8.8 Hz, 1H), 6.71 (s, 1H), 5.38 (s, 1H), 5.19- 5.02 (m,2H), 4.60-4.55 (m, 2H), 4.08-3.93 (m, 3H), 3.18 (s, 2H), 2.91-2.78 (m,1H), 2.64 (br. s., 4H), 2.00-1.96 (m, 1H)

Example 99 (SchemeNN)—(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(NN-5)

Step 1—Synthesis of tert-butyl((1S,4R)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)carbonate (NN-1)

Vial A:

To a dry round bottom flask (purged with N₂) was added(S,S)-DACH-Naphthyl Trost Ligand (1.13 g, 1.43 mmol) and Pd₂(dba)₃.CHCl₃(493 mg, 0.48 mmol). The vial was purged with N₂ four times and DCE (50mL, sparged with N₂ for 30 min) was added. The black solution wasstirred for 30 min at 12° C. at which point a red-brown solution wasobtained.

Vial B:

To a dry round bottom flask (purged with N₂) was added BB-1 (7155 mg,23.82 mmol), 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (4.5 g, 26.23mmol) and Cs₂CO₃ (8.54 g, 26.2 mmol). The vial was purged with N₂ fivetimes and DCE (50 mL) was added, followed by the addition of thecontents of Vial A via syringe. The reaction stirred at 12° C. under N₂for 24 hours.

The reaction mixture was filtered and concentrated to a brown gum. Thecrude residue was purified by flash biotage (120 g, silica gel,EtOAc/petroleum ether=15%) to give NN-1 (6.4 g, 76%) as an off-whitesolid. LCMS [M+1] 354; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.62 (s, 1H), 7.08(d, J=2.5 Hz, 1H), 6.35-6.29 (m, 1H), 6.10-6.00 (m, 2H), 5.63-5.55 (m,1H), 3.11 (td, J=7.8, 15.4 Hz, 1H), 1.87 (td, J=3.8, 15.0 Hz, 1H), 1.52(s, 9H)

Step 2—Synthesis of tert-butyl8-(((1S,4R)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(NN-2)

To a dry microwave vial (purged with N₂) was added NN-1 (200 mg, 0.57mmol), tert-butyl 8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(141 mg, 0.57 mmol), Cs₂CO₃ (203 mg, 0.622 mmol), Pd₂(dba)₃.CHCl₃ (15mg, 0.014 mmol) and DPPP (14 mg, 0.03 mmol). Then the vial was purgedwith N₂ three times and DCE (2.6 mL, sparged with N₂ for 30 mins) wasadded. The black mixture was stirred at 20° C. for 1 hour. Then thereaction mixture was directly purified by prep-TLC (petroleumether:EtOAc=4:1) to give NN-2 (260 mg, 95%) as a white foam.

LCMS [M+23] 507; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.63 (s, 1H), 7.16 (d,J=2.0 Hz, 1H), 7.14-7.09 (m, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.74 (d, J=7.5Hz, 1H), 6.46-6.40 (m, 1H), 6.15-6.06 (m, 2H), 5.37-5.31 (m, 1H),4.74-4.42 (m, 2H), 3.75-3.54 (m, 2H), 3.19-3.10 (m, 1H), 2.87-2.79 (m,2H), 1.97 (d, J=14.6 Hz, 1H), 1.51 (s, 9H)

Step 2—Synthesis of tert-butyl8-(((1S,2S,3S,4R)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(NN-3)

To a mixture of NN-2 (260 mg, 0.536 mmol) in DCM (9 mL)/H₂O (0.3 mL) wasadded NMO (188 mg, 1.61 mmol) and OsO₄ (4% in t-BuOH, 204 mg, 0.0322mmol) at 20° C. The black mixture was stirred at 20° C. for 2 hours. Themixture was diluted with DCM (10 mL) and quenched by sat. Na₂SO₃ (5 mL)and separated. The aqueous layer was extracted with DCM (10 mL). Thecombined organic layer was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated and purified by ISCO (12 g, silica gel,EtOAc:petroleum ether=1:1) to yield NN-3 (230 mg, 83%) as a colorlessgum.

LCMS [M+23] 541; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.62 (s, 1H), 7.17 (t,J=8.0 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 6.86-6.79 (m, 2H), 5.21-5.05 (m,1H), 5.02-4.75 (m, 2H), 4.67-4.56 (m, 1H), 4.53-4.42 (m, 2H), 4.37-4.29(m, 1H), 3.72-3.57 (m, 2H), 3.32-2.99 (m, 2H), 2.87-2.78 (m, 2H),2.33-2.22 (m, 1H), 1.50-1.44 (m, 9H)

Step 3—Synthesis of tert-butyl8-(((1S,2S,3S,4R)-4-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(NN-4)

A solution of NN-3 (105 mg, 0.202 mmol) in NH₃.H₂O and dioxane (2.8mL/2.8 mL) was sealed in a steel tube at 90° C. for 15 hours. Thereaction was concentrated to give NN-4 (101 mg, >99%) as a yellow gumand used directly in the next step. LCMS [M+23] 522

Step 4—Synthesis of(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(NN-5)

To a light yellow solution of NN-4 (101 mg, 0.202 mmol) in DCM (5 mL)was added TFA (1 mL) dropwise at 0° C. The yellow solution mixture wasstirred at 20° C. for 2 hours. The mixture was concentrated MeOH (4 mL)was added to the residue and basified by solid K₂CO₃ to pH 7-8. Themixture was filtered and concentrated purified by prep-HPLC to give NN-5(35 mg, 39%) as a light yellow solid.

LCMS [M+1] 400; ¹H NMR (400 MHz, MeOD) δ ppm 8.09 (s, 1H), 7.35-7.23 (m,1H), 7.15-7.06 (m, 1H), 7.03-6.96 (m, 1H), 6.94-6.83 (m, 1H), 5.16-5.07(m, 1H), 4.75-4.68 (m, 1H), 4.63-4.55 (m, 1H), 4.37 (s, 2H), 4.22-4.16(m, 1H), 3.54-3.44 (m, 2H), 3.17-3.08 (m, 2H), 3.04-2.92 (m, 1H),2.16-2.02 (m, 1H)

Examples 100-111 were made in a similar fashion to Example 99 in SchemeNN using the appropriate NBoc-protected tetrahydroisoquinoline in step2.

418 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.09 (s, 1H), 7.08 (d, J = 2.0 Hz, 1H),7.02-6.83 (m, 2H), 5.13 (q, J = 8.8 Hz, 1H), 4.68- 4.62 (m, 1H), 4.55(dd, J = 5.0, 8.8 Hz, 1H), 4.15 (d, J = 5.5 Hz, 1H), 4.13 (s, 2H), 3.26(t, J = 6.0 Hz, 2H), 3.01-2.92 (m, 1H), 2.89 (t, J = 6.1 Hz, 2H), 2.04(ddd, J = 4.3, 9.1, 14.0 Hz, 1H)

478 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-bromo-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.08 (s, 1H), 7.17-7.10 (m, 1H), 7.09-7.05 (m,1H), 7.04-7.00 (m, 1H), 5.10 (q, J = 8.8 Hz, 1H), 4.69-4.63 (m, 1H),4.57- 4.51 (m, 1H), 4.16-4.06 (m, 3H), 3.29- 3.24 (m, 2H), 2.99-2.89 (m,3H), 2.13- 2.02 (m, 1H)

434 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-chloro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.08 (s, 1H), 7.07 (d, J = 4.0 Hz, 2H), 6.93(s, 1H), 5.07 (q, J = 8.8 Hz, 1H), 4.72-4.63 (m, 1H), 4.60-4.53 (m, 1H),4.28 (s, 2H), 4.16-4.12 (m, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.06 (t, J =6.3 Hz, 2H), 2.99-2.88 (m, 1H), 2.19-2.04 (m, 1H)

436 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6-difluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.07 (s, 1H), 7.07 (d, J = 2.0 Hz, 1H),7.03 (dd, J = 6.7, 12.2 Hz, 1H), 5.06 (q, J = 9.0 Hz, 1H), 4.63 (td, J =2.6, 4.8 Hz, 1H), 4.55 (dd, J = 5.3, 8.8 Hz, 1H), 4.20 (s, 2H), 4.13 (d,J = 4.0 Hz, 1H), 3.40 (t, J = 6.3 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H),2.93 (td, J = 8.2, 14.3 Hz, 1H), 2.09 (ddd, J = 4.8, 9.3, 14.1 Hz, 1H)

468 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6- (trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.08 (s, 1H), 7.12 (s, 1H), 7.08 (d, J = 2.3 Hz, 1H),7.06 (s, 1H), 5.14 (q, J = 9.3 Hz, 1H), 4.74-4.67 (m, 1H), 4.52 (dd, J =5.0, 8.8 Hz, 1H), 4.13 (d, J = 5.5 Hz, 1H), 3.98 (s, 2H), 3.09-3.04 (m,2H), 2.95 (ddd, J = 7.3, 9.2, 14.4 Hz, 1H), 2.88-2.83 (m, 2H), 2.06(ddd, J = 4.1, 9.0, 13.7 Hz, 1H)

414 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-methyl-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.05 (s, 1H), 7.20 (s, 1H), 6.92 (br. s., 2H),6.66 (s, 1H), 6.53 (s, 1H), 5.06-4.98 (m, 1H), 4.50 (br. s., 1H),4.41-4.37 (m, 1H), 3.95-3.92 (m, 1H), 3.88 (br. s., 2H), 3.05- 2.95 (m,3H), 2.84-2.67 (m, 2H), 2.23 (s, 3H), 1.84-1.73 (m, 1H)

428 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.14 (s, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.85(s, 1H), 6.74 (s, 1H), 5.17 (q, J = 9.0 Hz, 1H), 4.74-4.66 (m, 1H), 4.56(dd, J = 4.9, 8.9 Hz, 1H), 4.30 (s, 2H), 4.15 (d, J = 5.0 Hz, 1H), 3.47(t, J = 6.4 Hz, 2H), 3.07 (t, J = 6.1 Hz, 2H), 3.02-2.92 (m, 1H), 2.64(q, J = 7.4 Hz, 2H), 2.12-2.02 (m, 1H), 1.23 (t, J = 7.7 Hz, 3H)

418 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-fluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.16 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 6.86(dd, J = 2.3, 10.8 Hz, 1H), 6.67 (d, J = 9.3 Hz, 1H), 5.21-5.12 (m, 1H),4.68 (t, J = 5.3 Hz, 1H), 4.56 (dd, J = 5.0, 9.0 Hz, 1H), 4.30 (s, 2H),4.15 (d, J = 4.8 Hz, 1H), 3.48 (t, J = 6.3 Hz, 2H), 3.10 (t, J = 6.0 Hz,2H), 3.02-2.91 (m, 1H), 2.12 (ddd, J = 4.6, 9.5, 14.0 Hz, 1H)

452 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-chloro-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.08 (s, 1H), 7.08 (d, J = 2.0 Hz, 1H),7.01 (d, J = 6.0 Hz, 1H), 5.16-5.09 (m, 1H), 4.63- 4.58 (m, 1H),4.53-4.47 (m, 1H), 4.14- 4.08 (m, 1H), 3.92 (s, 2H), 3.07 (t, J = 5.9Hz, 2H), 2.98-2.88 (m, 1H), 2.82-2.73 (m, 2H), 2.07-1.97 (m, 1H)

496 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol¹H NMR (400 MHz, MeOD) δ ppm 8.09 (s, 1 H), 7.04-7.20 (m, 2 H), 5.13 (m,J = 9.00 Hz, 1 H), 4.59-4.68 (m, 1 H), 4.52 (m, J = 8.80 Hz, 1 H), 4.13(d, J = 4.77 Hz, 1 H), 3.95 (s, 2 H), 3.11 (m, J = 6.00 Hz, 2 H),2.87-3.03 (m, 1 H), 2.81 (m, J = 5.80 Hz, 2 H), 1.97-2.13 (m, 1 H)Example 110 tert-butyl 4- hydroxyisoindoline- 2-carboxylate

386 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2,3-dihydro-1H-isoindol-4-yloxy)cyclopentane- 1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.09 (s, 1H), 7.45-7.38 (m, 1H), 7.14-7.07 (m, 2H),7.07-7.01 (m, 1H), 5.18-5.08 (m, 1H), 4.78-4.72 (m, 1H), 4.66 (s, 4H),4.58-4.52 (m, 1H), 4.20-4.15 (m, 1H), 3.03-2.92 (m, 1H), 2.13-2.02 (m,1H) Example 111 tert-butyl 5- hydroxy-3,4- dihydroisoquinoline-2(1H)-carboxylate

400 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1,2,3,4- tetrahydroisoquinolin-5-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.09 (s,1H), 7.29 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.04 (d, J =8.5 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 5.22-5.09 (m, 2H), 4.74-4.68 (m,1H), 4.57 (dd, J = 5.0, 8.5 Hz, 1H), 4.37 (s, 2H), 4.18 (d, J = 4.0 Hz,1H), 3.56 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.5 Hz, 2H), 3.04-2.93 (m,1H), 2.11- 1.98 (m, 1H)

(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-(1,1- difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD) δ ppm 8.29 (s, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.14 (s, 1H), 7.10(s, 1H), 5.27 (q, J = 9.0 Hz, 1H), 4.79- 4.75 (m, 1H), 4.60 (dd, J =5.0, 9.0 Hz, 1H), 4.39 (s, 2H), 4.17 (d, J = 4.8 Hz, 1H), 3.52 (t, J =6.3 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H), 3.00 (ddd, J = 7.7, 9.0, 14.2 Hz,1H), 2.17 (ddd, J = 4.1, 9.7, 14.1 Hz, 1H), 1.93 (t, J = 18.3 Hz, 3H)

432 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-6-methyl-1,2,3,4-tetahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹HNMR with formic acid (400 MHz, MeOD-d₄) δ ppm 8.50 (br s, 1H), 8.07 (s,1H), 7.07 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 6.3 Hz, 1H), 5.07 (q, J =8.7 Hz, 1H), 4.67- 4.61 (m, 1H), 4.55 (dd, J = 5.0, 8.8 Hz, 1H), 4.28(s, 2H), 4.16-4.11 (m, 1H), 3.49- 3.41 (m, 2H), 3.01 (t, J = 6.1 Hz,2H), 2.96- 2.87 (m, 1H), 2.27 (d, J = 1.8 Hz, 3H), 2.10-2.01 (m, 1H)

Example 114 (SchemeOO)—(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(OO-1)

Step 1—Synthesis of(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(OO-1)

A mixture of NN-5 (100 mg, 0.25 mmol), 37% CH₂O (31 mg, 0.38 mmol) andNaBH(OAc)₃ (212 mg, 1.0 mmol) in THF (6 mL) was stirred at 20° C. for 2hrs. The mixture was filtered and sent to prep-HPLC to give OO-1 (65 mg,53%) as a light yellow solid. LCMS 414 [M+1]; ¹H NMR (400 MHz, MeOD-d₄)δ ppm 8.10 (s, 1H), 7.34-7.27 (m, 1H), 7.16-7.10 (m, 1H), 7.03-6.97 (m,1H), 6.94-6.88 (m, 1H), 5.18-5.09 (m, 1H), 4.75-4.68 (m, 1H), 4.59-4.53(m, 1H), 4.42-4.34 (m, 2H), 4.21-4.16 (m, 1H), 3.55-3.46 (m, 2H),3.23-3.16 (m, 2H), 3.08 (s, 3H), 3.04-2.92 (m, 1H), 2.16-2.03 (m, 1H)

Examples 115 & 116 were made using similar procedures to Scheme 00 fromExamples 110 & 111 respectively.

Example 115

400 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(2-methyl-2,3-dihydro-1H-isoindol-4-yl)oxy]cyclopentane-1,2- diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.09 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.15-7.06 (m,2H), 7.02 (d, J = 7.5 Hz, 1H), 5.21-5.10 (m, 1H), 4.77- 4.70 (m, 1H),4.66 (d, J = 5.5 Hz, 4H), 4.53 (dd, J = 5.1, 8.7 Hz, 1H), 4.18 (d, J =5.0 Hz, 1H), 3.11 (s, 3H), 2.98 (ddd, J = 7.4, 9.0, 14.4 Hz, 1H), 2.05(ddd, J = 4.3, 9.3, 14.1 Hz, 1H) Example 116

414 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)cyclopentane-1,2- diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.09 (s, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 2.0Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.22-5.10(m, 1H), 4.71 (br. s., 1H), 4.56 (dd, J = 4.9, 8.7 Hz, 1H), 4.23 (br.s., 2H), 4.18 (d, J = 4.5 Hz, 1H), 3.46-3.37 (m, 2H), 3.10 (t, J = 6.1Hz, 2H), 2.99 (ddd, J = 7.5, 9.2, 14.4 Hz, 1H), 2.93 (s, 3H), 2.05 (s,1H)

Synthesis of 5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-3)

Step 1—Synthesis of 2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (PP-2)

To a solution of 2-chloro-7H-pyrrolo[2,3-d] pyrimidine (PP-1) (8.5 g, 55mmol) and selectfluor (29.4 g, 83.0 mmol) in CH₃CN (500 mL) was addedAcOH (100 mL) under N₂. The mixture was stirred at 70° C. for 16 hours.The color of the reaction became orange from yellow. The reactionconcentrated and azeotroped with toluene (30 mL×3). Then the solid wasdiluted with CH₂Cl₂/EtOAc (1/1, 200 mL) and stirred at room temperature(25° C.) for 16 hrs and filtered. The filtrate was concentrated andwashed with DCM to afford crude material as a brown solid. MBTE wasadded and stirred overnight and filtered to afford PP-2 (1.5 g, 15%) asa yellow solid. LCMS 172 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.89 (d,J=0.8 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H)

Step 2—Synthesis of 5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-3)

Pd(PPh₃)₄(835 mg, 0.723 mmol) was added to a solution PP-2 (2.48 g,14.46 mmol) in dry THF (36 mL) at 10° C. The suspension was degassedwith N₂. A solution of Me₃Al (2M, 14.5 mL, 28.9 mmol) was added to theabove mixture at −10° C. slowly. After the addition, the mixture washeated at 70° C. for 16 hours. The reaction mixture was added toice-water carefully. The mixture was diluted with EtOAc and filteredthrough celite. The filtrate was partitioned between EtOAc and H₂O. Theorganic layer was separated and washed with brine, dried over Na₂SO₄ andconcentrated to afford the crude product and purified via flash column(MeOH:DCM=1%-7.5%) to afford the product HG-3 (1.2 g, 55%) as a yellowsolid. LCMS 152 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 11.76 (br. s.,1H), 8.96 (s, 1H), 7.44 (t, J=2.5 Hz, 1H), 2.63 (s, 3H)

Synthesis of 5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-4)

To Pd(PPh₃)₄(2 g, 1.75 mmol) was added a solution of HG-2 (7.5 g, 43.7mmol) in dry THF (75 mL). The suspension was degassed with N₂. Asolution of AlMe₃ (43.7 mL, 87.5 mmol, 2M) was added to the abovemixture at ice-water. After the addition, the yellow solution was heatedat 80° C. for 16 h. The reaction mixture was quenched with ice andaqueous Rochelle salt. The mixture was partitioned between EtOAc andH₂O. The mixture was filtered and the filtrate cake was washed withEtOAc (100 mL×3). The organic layer was separated and dried over Na₂SO₄and concentrated then purified via flash column (MeOH:DCM=1%-4%) toafford the product. The product was triturated in DCM and filtered. Thefiltrate cake was washed with TBME and collected to afford the productHG-4 (2.00 g, 30%) as a yellow solid. The filtrate was concentratedpurified via flash column (MeOH:DCM=1%-5%) to afford the product. LCMS152 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 11.89 (br. s., 1H), 8.62 (s,1H), 7.48 (t, J=2.5 Hz, 1H), 2.70 (s, 3H)

Synthesis of 4-chloro-5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine(HG-5)

Step 1—Synthesis of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (RR-2)

A mixture of 2-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one(RR-1) (2.7 g, 18.1 mmol) in POCl₃ (35 mL) was heated at reflux for 4hours. The mixture was cooled to 20° C. and concentrated. To the residuewas added ice-water (20 mL) and basified by solid Na₂CO₃ to pH-8. Themixture was extracted with EtOAc (60 mL×2). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated to yield RR-2 (2.4 g, 78%) as an off-white solid. LCMS 168[M+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 10.70-10.41 (m, 1H), 7.36-7.29 (m,1H), 6.67-6.56 (m, 1H), 2.81 (s, 3H)

Step 2—Synthesis of4-chloro-5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-5)

A mixture of RR-2 (2.35 g, 14 mmol) and Selectfluor (7.45 g, 21 mmol) inCH₃CN (110 mL) and AcOH (22 mL) was stirred at 70° C. under N₂ for 16hours in which the reaction became brown from pink. The mixture wasconcentrated and azeotroped toluene (50 ml×2). The filtrate wasconcentrated and purified by prep-HPLC to give HG-5 (600 mg, 23%) as ayellow solid. LCMS 186 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm12.27-12.18 (m, 1H), 7.62-7.56 (m, 1H), 2.61 (s, 3H)

Examples 117-119 were made in a similar fashion to CC-3 (Example 78)using the appropriate pyrrolopyrimidine in step 1 of Scheme BB and theappropriate N-Boc protected tetrahydroisoquinoline in step 1 of SchemeCC.

399 [M + 1] (1S,2S,3R,5S)-3-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.62 (s,1H), 8.50 (br. s., 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.27 (t, J = 7.8 Hz,1H), 6.97 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 5.23 (q, J =9.0 Hz, 1H), 4.74-4.69 (m, 1H), 4.69-4.62 (m, 1H), 4.36 (s, 2H), 4.18(d, J = 4.5 Hz, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H),3.04-2.90 (m, 1H), 2.78 (s, 3H), 2.21-2.07 (m, 1H)

367 [M + 1] (1S,2S,3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.00 (s,1H), 8.79 (s, 1H), 7.70 (d, J = 3.6 Hz, 1H), 7.12-7.03 (m, 1H),6.87-6.78 (d, J = 8.0, 1H), 6.78-6.62 (m, 2H), 5.39-5.32 (m, 1H),5.21-5.07 (m, 2H), 4.63-4.51 (m, 2H), 4.02-3.97 (m, 1H), 3.93- 3.81 (m,2H), 3.00-2.91 (m, 2H), 2.90-2.82 (m, 1H), 2.71-2.68 (m, 1H), 2.00-1.89(m, 1H)

424 M + 1 8-(((1S,2S,3S,4R)-4-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,3-dihydroxycyclopentyl)oxy)-1,2,3,4-tetrahydroisoquinoline-6- carbonitrile ¹H NMR with formic acid(400 MHz, DMSO-d₆) δ ppm 8.66 (s, 1H), 8.28 (s, 1H), 7.71 (s, 1H), 7.28(s, 1H), 7.20 (s, 1H), 5.14 (q, J = 9.6 Hz, 1H), 4.63-4.60 (m, 1H), 4.45(dd, J = 4.8, 9.0 Hz, 1H), 3.96 (d, J = 4.8 Hz, 1H), 3.89 (s, 2H),2.95-2.90 (m, 2H), 2.88-2.80 (m, 1H), 2.70- 2.67 (m, 5H), 1.95-1.90 (m,1H)

Examples 120 was made in a similar fashion to NN-5 (Example 99) usingthe appropriate pyrrolopyrimidine in step 1 of Scheme BB and theappropriate N-Boc protected tetrahydroisoquinoline in step 1 of SchemeNN.

485 [M + 1] 8-(((1S,2S,3S,4R)-4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,3-dihydroxycyclopentyl)oxy)-1,2,3,4-tetrahydroisoquinoline-6- carbonitrile ¹H NMR (400 MHz, MeOD-d₄)δ ppm 8.12 (s, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 5.05 (q, J= 9.2 Hz, 1H), 4.81-4.74 (m, 1H), 4.67 (dd, J = 4.9, 8.9 Hz, 1H), 4.38(s, 2H), 4.18 (br d, J = 4.3 Hz, 1H), 3.48 (t, J = 6.0 Hz, 2H), 3.13 (brt, J = 5.9 Hz, 2H), 3.03-2.93 (m, 1H), 2.26- 2.19 (m, 1H)

Example 121 (SchemeSS)—(1S,2S,3R,5S)-3-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(SS-5)

Step 1: Synthesis of tert-butyl8-(((1S,4R)-4-((tert-butoxycarbonyl)oxy)cyclopent-2-en-1-yl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(SS-1)

Vial A:

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was addedTris(benzylideneacetone)dipalladium(0)chloroform adduct (62 mg, 0.060mmol) and MFCD02684551 (R,R)-DACH-Naphthyl Trost Ligand (142 mg, 0.180mmol).

The vial was vacuum purged with argon under dynamic vacuum and DCE (5.0mL), which had been sparged with argon for 30 minutes, was added. Thesolution was stirred for 30 minutes at rt at which point a bright orangesolution of ligated catalyst was obtained. At this stage Vial B wasprepared.

Vial B:

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was added TP-2 (800 mg, 2.99 mmol), anddi-tert-butyl-((1R,3S)-cyclopent-4-ene-1,3-diyl)-bis(carbonate) (BB-1)(prepared as reported in J. Am. Chem. Soc. 2006, 128, 6054-6055) (1.08g, 3.59 mmol). The vial was vacuum purged with argon under dynamicvacuum and DCE (5.0 mL), which had been sparged with argon for 30minutes, was added followed by the addition of the contents of Vial Avia airtight syringe. The reaction was stirred under argon at rt for 12hours. The reaction was concentrated under vacuum and purified via flashcolumn chromatography (24g SiO2, Isco, 100% Hept. to 100% EtOAc, 20 mLfractions) to afford SS-1 (1.33 g, >95%) as a pale yellow solid. LCMS[M+H-Boc-isobutylene]=294 observed; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm6.84 (t, J=8.8 Hz, 1H), 6.65 (dd, J=4.3, 8.9 Hz, 1H), 6.20 (td, J=1.5,5.7 Hz, 1H), 6.17-6.11 (m, 1H), 5.46 (t, J=5.9 Hz, 1H), 5.09 (t, J=5.6Hz, 1H), 4.57-4.40 (m, 2H), 3.72-3.54 (m, 2H), 3.02 (td, J=7.4, 14.5 Hz,1H), 2.77 (t, J=5.7 Hz, 2H), 1.94 (td, J=4.5, 14.4 Hz, 1H), 1.50 (d,J=1.6 Hz, 18H).

Step 2: Synthesis of tert-butyl8-(((1S,4R)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(SS-2)

To a scintillation vial, equipped with a magnetic stirbar, was addedHG-6 (113 mg, 0.674 mmol), SS-1 (303 mg, 0.674 mmol),diphenylphosphinopropane (dppp) (13.9 mg, 0.034 mmol),tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (14 mg, 0.014mmol) and cesium carbonate (242 mg, 0.741 mmol). The vial was purgedwith argon under dynamic vacuum followed by the addition of DCE (2.25mL) which had been sparged with argon for 30 minutes. The reaction wasstirred at rt under argon for 1.5 hours. The reaction was transferred toa separatory funnel with DCM and diluted with water. The phases wereseparated and the aqueous phase was extracted with 2 portions DCM. Thecombined organic phases were dried (MgSO4), filtered, and concentratedunder vacuum. The crude residue was purified via flash columnchromatography (12g SiO2, Isco, 100% Hept. to 100% EtOAc, 9 mLfractions) to afford SS-2 (287.6 mg, 86%) as a colorless gum. LCMS[M+H]=499 observed; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.57 (s, 1H),7.14 (s, 1H), 6.86 (t, J=8.8 Hz, 1H), 6.68 (dd, J=3.7, 8.4 Hz, 1H), 6.37(d, J=5.4 Hz, 1H), 6.11 (d, J=4.4 Hz, 1H), 6.06-5.96 (m, 1H), 5.33-5.25(m, 1H), 4.69-4.41 (m, 2H), 3.75-3.55 (m, 2H), 3.22-3.03 (m, 1H), 2.79(t, J=5.4 Hz, 2H), 2.49 (s, 3H), 1.95 (td, J=3.6, 14.8 Hz, 1H), 1.51 (s,9H).

Step 3: Synthesis of tert-butyl8-(((1S,2S,3S,4R)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(SS-3)

To a scintillation vial, equipped with a magnetic stirbar and containingSS-2 (278 mg, 0.557 mmol), was added DCM (2.79 mL). To the solution wasadded 4-Methylmorpholine-N-oxide (NMO) (0.13 mL, 0.613 mmol) as a 50 wt% solution in water followed by the dropwise addition of osmiumtetraoxide (100 μL, 0.022 mmol) as a 4 wt % solution in water. Thereaction was stirred at rt for 4 hours. The reaction was transferred toa separatory funnel with DCM, diluted with water and further dilutedwith 1M NaHSO3. The phases were separated and the aqueous phase wasextracted with 3 portions of DCM. The combined organic extracts weredried (MgSO4), filtered, and concentrated under vacuum. The cruderesidue was purified via flash column chromatography (12g SiO2, Isco,100% Hept. to 100% EtOAc, 9 mL fractions) to afford SS-3 (169 mg, 57%)as a white solid. LCMS [M+H]=533 observed; 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.49 (s, 1H), 7.09 (br. s., 1H), 6.89 (t, J=8.8 Hz,1H), 6.81 (dd, J=4.2, 8.8 Hz, 1H), 5.03 (q, J=8.9 Hz, 1H), 4.73 (t,J=5.2 Hz, 1H), 4.55 (dd, J=5.2, 8.1 Hz, 1H), 4.53-4.40 (m, 2H), 4.30 (d,J=4.5 Hz, 1H), 3.73-3.54 (m, 2H), 3.13-2.97 (m, 1H), 2.79 (t, J=5.7 Hz,2H), 2.49 (s, 3H), 2.31 (ddd, J=4.6, 9.4, 14.1 Hz, 1H), 1.48 (br. s.,9H).

Step 4: Synthesis of tert-butyl8-(((1S,2S,3S,4R)-4-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(SS-4)

To a reaction vial, equipped with a magnetic stirbar, was added SS-3(159 mg, 0.298 mmol) as a solution in dioxane (0.8 mL) and ammoniumhydroxide (0.8 mL, 5.00 mmol). The reaction was placed in a microwavereactor and heated to 120° C. for 6 hours. The solution was transferredto a separatory funnel with DCM and diluted with water. The phases wereseparated and the aqueous phase was extracted with 3 portions of a 3:1mixture of DCM:IPA. The combined organic extracts were dried (MgSO4),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (12g SiO2, Isco, 100% Hept. to 10%MeOH/EtOAc, 9 mL fractions) to afford SS-4 (98.4 mg, 64%) as a whitesolid. LCMS [M+H]=514 observed; [α]²² _(D)=−70.0° (C=0.1, MeOH); 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.13 (s, 1H), 6.98-6.81 (m, 2H), 6.76 (br.s., 1H), 5.32 (br. s., 2H), 4.93-4.80 (m, 1H), 4.73 (t, J=5.3 Hz, 1H),4.54 (br. s., 1H), 4.44 (d, J=16.8 Hz, 2H), 4.25 (br. s., 1H), 3.75-3.51(m, 2H), 3.11-2.92 (m, 1H), 2.79 (t, J=5.5 Hz, 2H), 2.43 (s, 3H),2.38-2.25 (m, 1H), 1.48 (br. s., 9H).

Step 5: Synthesis of(1S,2S,3R,5S)-3-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(SS-5)

To a scintillation vial, equipped with a magnetic stirbar and containingSS-4 (79.4 mg, 0.155 mmol), was added dioxane (0.4 mL). To the solutionwas added hydrochloric acid (0.4 mL) as a 4M solution in dioxane and thereaction was stirred at rt for 17 hours. The reaction was quenched withhalf saturated NaHCO₃ aqueous and transferred to a separatory funnelwith DCM. The phases were separated and the aqueous phase was extractedwith 3 portions of 3:1 mixture of DCM/IPA. The combined organic extractswere dried (MgSO4), filtered, and concentrated under vacuum. Theisolated material was dissolved in a minimum amount of methanol anddiluted with water. The sample was frozen and lyophilized overnight toafford SS-5 (51.3 mg, 80%) as a white solid. LCMS [M+H] 414 observed; 1HNMR (400 MHz, METHANOL-d4) δ ppm 8.03 (s, 1H), 6.98 (d, J=1.0 Hz, 1H),6.93-6.81 (m, 2H), 5.07 (q, J=8.7 Hz, 1H), 4.62 (ddd, J=1.8, 4.0, 7.0Hz, 1H), 4.51 (dd, J=5.0, 8.5 Hz, 1H), 4.17-4.11 (m, 1H), 3.98 (s, 2H),3.10 (t, J=6.0 Hz, 2H), 2.93 (ddd, J=7.3, 9.3, 14.5 Hz, 1H), 2.77 (t,J=5.9 Hz, 2H), 2.43 (d, J=1.1 Hz, 3H), 1.99 (ddd, J=4.0, 8.4, 13.8 Hz,1H); 19F NMR (376 MHz, METHANOL-d4) d=−131.36 (s, 1F).

Examples 122-129 were made in a similar fashion to SS-5 (Example 121)using the appropriate N-Boc protected tetrahydroisoquinoline in step 1 Sand the appropriate pyrrolopyrimidine in step 2 of Scheme SS.

410 M + 1 (1S,2S,3R,5S)-3-(4-amino-5- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-methyl-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.05 (s, 1H), 6.99 (s, 1 H), 6.70 (s, 1 H), 6.61 (s, 1 H), 5.17- 5.06 (m, 1 H),4.71-4.64 (m, 1 H), 4.53 (dd, J = 8.53, 4.77 Hz, 1 H), 4.16 (d, J = 4.27Hz, 1 H), 3.99 (s, 2 H), 3.12 (d, J = 5.90 Hz, 2 H), 2.97 (dd, J =14.50, 9.50, 7.20 Hz, 1 H), 2.83 (t, J = 5.77 Hz, 2 H), 2.45 (s, 3 H),2.30 (s, 3 H), 2.04-1.93 (m, 1 H)

474 M + 1 (1S,2S,3R,5S)-3-(4-amino-5- bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-methyl-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.12 (s,1H), 7.35 (s, 1H), 6.77 (s, 1H), 6.67 (s, 1H), 5.11 (q, J = 9.0 Hz, 1H),4.69 (ddd, J = 1.6, 4.0, 7.2 Hz, 1H), 4.62 (dd, J = 4.8, 8.8 Hz, 1H),4.18-4.13 (m, 3H), 3.31-3.27 (m, 2H), 3.03-2.92 (m, 3H), 2.33 (s, 3H),2.14-2.06 (m, 1H)

413 M + 1 (1S,2S,3R,5S)-3-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((6-methyl-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.65 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 6.81 (s, 1H),6.70 (s, 1H), 5.25 (q, J = 9.0 Hz, 1H), 4.71 (dt, J = 2.3, 3.6 Hz, 1H),4.69-4.64 (m, 1H), 4.26 (s, 2H), 4.17 (d, J = 4.8 Hz, 1H), 3.39 (t, J =6.1 Hz, 2H), 3.04-2.95 (m, 3H), 2.80 (s, 3H), 2.34 (s, 3H), 2.20-2.11(m, 1H)

497 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((5,6-difluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.10 (s, 1H), 7.35 (s, 1H), 6.87 (dd, J = 6.8, 12.5 Hz,1H), 5.09 (q, J = 8.8 Hz, 1H), 4.58-4.51 (m, 2H), 4.13 (d, J = 5.0 Hz,1H), 3.90 (s, 2H), 3.12-3.01 (m, 2H), 3.00- 2.90 (m, 1H), 2.78 (t, J =5.8 Hz, 2H), 2.13-2.00 (m, 1H)

432 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5- fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro- 1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.07 (br.s., 2H), 7.27 (br. s., 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.99 (dd, J = 4.1,9.2 Hz, 1H), 5.38 (br. s., 1H), 5.18 (br. s., 1H), 5.08 (q, J = 9.0 Hz,1H), 4.53 (br. s., 1H), 4.39-4.30 (m, 1H), 4.21 (br. s., 2H), 3.95 (br.s., 1H), 2.95-2.88 (m, 2H), 2.83-2.73 (m, 1H), 2.53- 2.51 (m, 3H), 2.40(s, 3H), 1.74 (ddd, J = 4.4, 9.3, 13.7 Hz, 1H)

413 [M + 1] (1S,2S,3R,5S)-3-(5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((6-methyl-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.90 (s, 1H), 7.39 (s, 1H), 6.76 (s, 1H), 6.66 (s, 1H),5.35 (q, J = 9.2 Hz, 2H), 4.58 (dd, J = 4.9, 8.7 Hz, 1H), 4.17 (d, J =4.3 Hz, 1H), 4.12 (s, 2H), 3.25 (t, J = 6.0 Hz, 2H), 3.06-2.95 (m, 1H),2.92 (t, J = 5.9 Hz, 2H), 2.74 (s, 3H), 2.33 (s, 3H), 2.13-2.04 (m, 1H)

452 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((5,6-difluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz,MeOD-d4) δ ppm 8.09 (s, 1H), 7.29 (s, 1H), 6.89 (dd, J = 6.7, 12.4 Hz,1H), 5.15- 5.01 (m, 1H), 4.60-4.50 (m, 2H), 4.16-4.07 (m, 1H), 3.94 (s,2H), 3.11 (t, J = 6.0 Hz, 2H), 2.99-2.88 (m, 1H), 2.81 (t, J = 5.8 Hz,2H), 2.12-2.02 (m, 1H)

430 M + 1 (1S,2S,3R,5S)-3-(4-amino-5- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-methyl-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.12 (s,1H), 7.30 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.08 (q, J = 9.0 Hz, 1H),4.74-4.68 (m, 1H), 4.64 (dd, J = 5.0, 8.8 Hz, 1H), 4.28 (s, 2H), 4.17(d, J = 4.8 Hz, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.05 (t, J = 6.1 Hz, 2H),2.98 (ddd, J = 7.4, 9.1, 14.4 Hz, 1H), 2.35 (s, 3H), 2.12 (ddd, J = 4.0,9.3, 14.0 Hz, 1H)

Examples 130-132 were prepared using the chemistry depicted in Scheme SSby employing the appropriate tetrahydroisoquinoline for step 1 andpyrrolopyrimidine for step 2. In a modification to step 5,trifluoroacetic acid (TFA) was used for the deprotection.

Example 130 (SchemeTT)—(1S,2S,3R,5S)-3-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(TT-2)

To a cooled solution of TT-1 (50.0 mg, 0.091 mmol) in DCM (2.0 mL) wasadded TFA (0.50 mL). The yellow solution was stirred at 15° C. for 1hour. The reaction was concentrated under vacuum to give the crudeproduct and the pH of the solution was adjusted to 7-8 using saturatedNaHCO₃ aq. (2 mL). Then FA (1%) aq. (2 mL) was added to the reactionsolution. The mixture was purified by prep-HPLC and the desiredfractions were combined and lyophilized to afford TT-2 (35.0 mg, 86%) aswhite solid.

450 observed [M + H] (1S,2S,3S,5R)-3-((6- chloro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol 1H NMR (400 MHz,DMSO-d6) δ ppm 8.04 (s, 1H), 7.38 (s, 1H), 7.01- 6.89 (m, 2H), 4.92 (q,J = 9.0 Hz, 1H), 4.56 (d, J = 5.3 Hz, 1H), 4.47 (dd, J = 4.9, 9.2 Hz,1H), 4.13 (s, 2H), 3.95 (d, J = 4.8 Hz, 1H), 3.29 (t, J = 6.1 Hz, 2H),2.94 (t, J = 5.9 Hz, 2H), 2.86- 2.76 (m, 1H), 1.89 (ddd, J = 3.9, 9.5,13.7 Hz, 1H)

495 observed [M + H] (1S,2S,3R,5S)-3-(5- bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-5-((6-chloro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2- diol 1H NMR (400 MHz,DMSO-d6) δ ppm 8.10 (s, 1H), 7.53 (s, 1H), 6.92 (d, J = 1.5 Hz, 1H),6.85-6.57 (m, 2H), 5.36 (br. s., 1H), 5.16 (br. s., 1H), 4.99 (q, J =9.2 Hz, 1H), 4.58-4.51 (m, 1H), 4.50-4.42 (m, 1H), 3.93 (d, J = 5.0 Hz,1H), 3.79 (s, 2H), 2.91 (t, J = 5.8 Hz, 2H), 2.84-2.73 (m, 1H),2.70-2.62 (m, 2H), 1.96-1.84 (m, 1H)

417 observed [M + H] (1S,2S,3S,5R)-3-((5- fluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(5-fluoro-2- methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol 1H NMR (400 MHz, METHANOL-d4) δppm 8.87 (d, J = 0.8 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 6.92-6.81 (m,2H), 5.37- 5.27 (m, 1H), 4.65-4.60 (m, 1H), 4.56 (t, J = 8.9 Hz, 1H),4.14 (d, J = 5.0 Hz, 1H), 3.96 (s, 2H), 3.10- 3.04 (m, J = 6.0, 6.0 Hz,2H), 3.01-2.91 (m, J = 7.2, 9.4, 14.6 Hz, 1H), 2.79- 2.73 (m, J = 6.0,6.0 Hz, 2H), 2.72 (s, 3H), 2.11- 2.03 (m, 1H)

Examples 133 & 134 were prepared using the chemistry depicted in SchemeSS by employing the appropriate tetrahydroisoquinoline for step 1 andpyrrolopyrimidine for step 2. In a modification to the general procedurefor step 4, HOBt was employed as a catalyst as described in Scheme UU.

Synthesis of tert-butyl8-(((1S,2S,3S,4R)-4-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(UU-2)

To a reaction vial, equipped with a magnetic stirbar, was added UU-1(147 mg, 0.266) as a solution in DMA (2.5 mL) followed by the additionof HOBt.hydrate (8.13 mg, 0.053 mmol). To the solution was addedammonium hydroxide (1.0 mL, 7.96 mmol). The vial was sealed with ateflon cap and placed in a heating block. The reaction was heated at100° C. for 19 hours. The solution was transferred to a separatoryfunnel with DCM and diluted with water. The phases were separated andthe aqueous phase was extracted with 3 portions of DCM. The combinedorganic extracts were dried (MgSO4), filtered, and concentrated undervacuum. The crude residue was purified via flash column chromatography(4g SiO2, Isco, 100% Hept. to 10% MeOH/EtOAc, 9 mL fractions). Fractionscontaining product were collected and concentrated under vacuum. Thematerial was lyophilized to afford the product, containing minorimpurities, as an off-white solid (140.7 mg, 99%). The material was usedin step 5, employing TFA/DCM for the deprotection as depicted in schemeTT, without further purification.

434 observed [M + H] (1S,2S,3R,5S)-3-(4- amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((5-fluoro- 1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane- 1,2-diol 1H NMR (700 MHz,DMSO-d6) δ ppm 8.08 (br. s., 1H), 7.44 (s, 1H), 6.97-6.89 (m, 1H), 6.82(d, J = 4.6 Hz, 1H), 5.26 (br. s., 1H), 5.11 (br. s., 1H), 4.99 (q, J =8.6 Hz, 1H), 4.55- 4.39 (m, 2H), 3.94 (br. s., 1H), 3.83 (br. s., 2H),2.93 (br. s., 2H), 2.84- 2.70 (m, 2H), 2.58 (br. s., 2H), 1.92-1.82 (m,1H).

478 observed [M + H] (1S,2S,3R,5S)-3-(4- amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((5-fluoro- 1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane- 1,2-diol 1H NMR (700 MHz,DMOS-d6) δ ppm (s, 1H), 7.49 (s, 1H), 6.94- 6.88 (m, 1H), 6.84- 6.77 (m,1H), 5.25 (br. s., 1H), 5.15-5.05 (m, 1H), 4.99 (d, J = 9.0 Hz, 1H),4.47 (d, J = 3.3 Hz, 2H), 3.94 (br. s., 1H), 3.81 (br. s., 2H), 2.92(br. s., 2H), 2.80-2.70 (m, 1H), 2.58 (br. s., 2H), 1.86 (br. s., 1H).

Example 135 (SchemeW)—(1S,2S,3S,5R)-3-(4-fluoro-2-(hydroxymethyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(2)

Compound W-1 was prepared using procedures from steps 2 and 3 fromScheme BB starting from BB-2 and using commercially available methyl5-fluoro-2-hydroxybenzoate. To a solution of W-1 (90 mg, 0.22 mmol) indry THF (5 mL) was added LiAlH₄ (30 mg, 0.79 mmol) at 0° C. for 2 hours.H₂O (30 mL) was added to the reaction mixture and the mixture wasextracted with EtOAc (30 mL×4). The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo to a residue that waspurified by prep-TLC giving W-2 (60 mg, 72%) as a white solid. LCMS 374[M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1H), 7.65 (d, J=3.8 Hz,1H), 7.18 (d, J=9.0 Hz, 1H), 7.04-6.99 (m, 2H), 6.72 (d, J=3.5 Hz, 1H),5.32 (d, J=3.8 Hz, 1H), 5.23 (t, J=5.6 Hz, 1H), 5.16-5.07 (m, 2H), 4.58(d, J=5.8 Hz, 2H), 4.56-4.50 (m, 2H), 3.99 (br. s., 1H), 2.88-2.78 (m,1H), 2.64 (s, 3H), 1.97-1.87 (m, 1H)

Example 136 (SchemeWW)—(1S,2S,3S,5R)-3-(4-fluoro-2-hydroxyphenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(WW-6)

Step 1—Synthesis of1-(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)ethan-1-one(WW-2)

Compound WW-1 was prepared using procedures from steps 2 and 3 fromScheme BB starting from BB-2 and using commercially available1-(5-fluoro-2-hydroxyphenyl)ethan-1-one. To a stirred white suspensionsolution of WW-1 (1.06 g, 2.75 mmol) in acetone (6 mL) was added2,2-dimethoxypropane (16 mL) and p-toluenesulfonic acid (523 mg, 2.75mmol) at r.t (25° C.). The reaction was stirred at 25° C. for 15 hrs.Aqueous NaHCO₃ was added to the reaction mixture until the pH reached8.0. Then the mixture was extracted with EtOAc (15 mL×5). The organiclayers were separated, dried and evaporated to give the crude product,which was purified by chromatography, eluted with MeOH/DCM 0-5% to giveWW-2 (1.06 g, 91%) as a white solid. The material was used directly inthe next step.

Step 2—Synthesis of7-((3aS,4R,6S,6aR)-6-(2-acetyl-4-fluorophenoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine3-oxide (WW-3)

Compound WW-2 (1.03 g, 2.42 mmol) was dissolved in DCM (15 mL). Thenm-CPBA (1.97 g, 9.68 mmol) was added to the above mixture. The reactionmixture was heated at 40° C. for 16 hours. The mixture was cooled to 25°C. Then the mixture was diluted with DCM (15 mL) and then saturatedsodium thiosulfate (15 mL) was added the organic layer was separated.The organic layer was washed with saturated NaHCO₃ (20 mL), dried overNa₂SO₄, filtered and purified by flash chromatography eluted with from0-10% MeOH/DCM to give WW-3 (600 mg, 56%) as a yellow oil and useddirectly in the next step.

Step 3—Synthesis of7-((1R,2S,3S,4S)-4-(2-acetoxy-4-fluorophenoxy)-2,3-dihydroxycyclopentyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine3-oxide (WW-4)

Trifluoroacetic anhydride (3.56 g, 16.9 mmol) was cooled to −10° C. forabout 10-20 min and 30% H₂O₂(457 mg, 3.13 mL) was added drop-wise andstirred for 10 min (maintaining the temperature between 0 and −10° C.).To this mixture was added compound WW-3 (570 mg, 1.29 mmol) in DCM (5mL) drop-wise and stirred at 25° C. for 10-30 min. SaturatedNa₂S2O₃/NaHCO₃ aq (15 mL) was added to the above mixture and stirred at25° C. for 10 min.

The reaction solution was extracted with DCM (10 mL×2), dried andevaporated to give the crude WW-4 (540 mg, >99%) as a yellow oil. LCMS418 [M+1]

Step 4—Synthesis of2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorophenylacetate (WW-5)

Compound WW-4 (540 mg, 1.22 mmol) was dissolved in DMF (1 mL). Thenhypodiboric acid (658 mg, 7.34 mmol) was added to the above mixture andstirred at 25° C. for 30 min. The reaction solution of WW-5 was useddirectly for the next step without further purification. LCMS 402 [M+1]

Step 5—Synthesis of(1S,2S,3S,5R)-3-(4-fluoro-2-hydroxyphenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (WW-6)

A solution of compound WW-5 (490 mg, 1.11 mmol) in DMF was added MeOH (2mL). K₂CO₃ (2.30 g, 16.6 mmol) was added to the above mixture. Thereaction mixture was stirred at 25° C. for 2 hours. The solvent wasevaporated and the crude product was purified by prep-HPLC to give WW-6(62 mg, 16%) as a white solid. LCMS 360 [M+1]; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 9.53 (s, 1H), 8.63 (s, 1H), 7.75 (d, J=3.5 Hz, 1H), 7.01 (dd,J=5.9, 8.9 Hz, 1H), 6.75 (d, J=3.8 Hz, 1H), 6.68 (d, J=3.0 Hz, 1H), 6.66(d, J=3.0 Hz, 1H), 6.56 (dt, J=3.0, 8.7 Hz, 1H), 5.26 (d, J=3.0 Hz, 1H),5.16 (q, J=8.9 Hz, 1H), 5.07 (d, J=6.8 Hz, 1H), 4.54 (br. s., 2H), 4.00(br. s., 1H), 2.83-2.74 (m, 1H), 2.65 (s, 3H), 1.97-1.90 (m, 1H)

Example 137 (SchemeXX)—(1S,2S,3S,5R)-3-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(XX-3) Example 138 (SchemeXX)—(1S,2S,3S,5R)-3-(2-((S)-1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(XX-4)

Step 1—Synthesis of1-(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)ethan-1-amine(XX-1)

Compound WW-2 (100 mg, 0.235 mmol) was dissolved in MeOH (1 mL). ThenNH₄OAc (181 mg, 2.35 mmol) was added to the above mixture and stirred at25° C. for 1 hour. Then NaBH₃CN (89 mg, 1.41 mmol) was added and heatedto 80° C. for 16 hour. The mixture was cooled to 25° C., then 1 mLsaturated NaHCO₃ was added and stirred 25° C. for 10 min. The reactionmixture was extracted with DCM (5 mL×3), separated, dried and evaporatedto give crude material which was purified by prep-TLC (MeOH/DCM 0-10%)to afford XX-1 (35 mg, 35%) as a colorless oil and used directly in thenext step.

Step 2—Synthesis of(1S,2S,3S,5R)-3-(2-(1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (XX-2)

To compound XX-1 (100 mg, 0.234 mmol) in H₂O (0.5 mL) was added TFA (0.5mL) at 0° C. The mixture was stirred at 0° C. for 60 min. The pH of thereaction solution was adjusted to pH=9 by addition of saturated K₂CO₃aq. The final solution was separated by prep-HPLC, to give 90 mg of theXX-2 (90 mg, 99%) as a white solid.

Step 3—Separation of(1S,2S,3S,5R)-3-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(XX-3) and(1S,2S,3S,5R)-3-(2-((S)-1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(XX-4)

Separation of compound XX-2 by chiral SFC

XX-3: LCMS 370 [M-NH₂]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (s, 1H),7.61 (d, J=3.7 Hz, 1H), 7.29 (dd, J=3.0, 10.0 Hz, 1H), 7.03-6.90 (m,2H), 6.72 (d, J=3.7 Hz, 1H), 5.34 (br. s., 1H), 5.18-5.01 (m, 2H),4.61-4.49 (m, 2H), 4.33 (q, J=6.4 Hz, 1H), 4.01 (d, J=4.5 Hz, 1H),2.94-2.79 (m, 1H), 2.64 (s, 3H), 2.00 (ddd, J=4.0, 9.4, 13.8 Hz, 2H),1.25 (d, J=6.5 Hz, 3H)

XX-4: LCMS 370 [M-NH₂]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1H),7.60 (d, J=3.7 Hz, 1H), 7.29 (dd, J=3.0, 10.0 Hz, 1H), 7.04-6.87 (m,2H), 6.71 (d, J=3.5 Hz, 1H), 5.35 (br. s., 1H), 5.20-5.03 (m, 2H),4.63-4.46 (m, 2H), 4.33 (q, J=6.6 Hz, 1H), 4.02 (d, J=4.3 Hz, 1H),2.91-2.78 (m, 1H), 2.64 (s, 3H), 2.04-1.91 (m, 2H), 1.26 (d, J=6.6 Hz,3H)

Examples 139-142 were made in a similar fashion as XX-3 & XX-4 startingfrom BB-2 and the appropriate phenolic ketone. The sequence starts withsteps 2 (allylic alkylation) & 3 (dihydroxylation) from Scheme BBfollowed by step 1 (acetonide formation) from Scheme WW and then steps 1(reductive amination), 2 (deprotection) and 3 (chiral separation) inScheme XX.

421 [M + 1] (1S,2S,3S,5R)-3-(2-((S)-1- aminoethyl)-5-chloro-4-fluorophenoxy)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.61 (s, 1H),7.55 (d, J = 3.5 Hz, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.20 (d, J = 6.3Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 5.16 (q, J = 9.0 Hz, 1H), 4.80-4.73(m, 1H), 4.72-4.64 (m, 1H), 4.49-4.39 (m, 1H), 4.22 (d, J = 5.0 Hz, 1H),3.04-2.92 (m, 1H), 2.72 (s, 3H), 2.36-2.25 (m, 1H), 1.44 (d, J = 6.8 Hz,3H)

421 [M + 1] (1S,2S,3S,5R)-3-(2-((R)-1- aminoethyl)-5-chloro-4-fluorophenoxy)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.62 (s, 1H),7.56 (d, J = 3.5 Hz, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.19 (d, J = 6.0Hz, 1H), 6.75 (d, J = 3.8 Hz, 1H), 5.17 (q, J = 9.0 Hz, 1H), 4.79 (dd, J= 5.0, 8.8 Hz, 1H), 4.69 (br. s., 1H), 4.42 (q, J = 6.8 Hz, 1H), 4.20(d, J = 4.8 Hz, 1H), 3.06-2.93 (m, 1H), 2.72 (s, 3H), 2.41-2.28 (m, 1H),1.45 (d, J = 6.8 Hz, 3H)

364 [M − NH₂] (1S,2S,3S,5R)-3-(((S)-3-amino-2,3-dihydro-1H-inden-4-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (s, 1H),7.67 (d, J = 3.5 Hz, 1 H), 7.21-7.06 (m, 1H), 6.86-6.77 (m, 2H), 6.71(d, J = 3.5 Hz, 1H), 5.40 (br. s., 1H), 5.15-5.04 (m, 2H), 4.65-4.57 (m,2H), 4.51-4.45 (m, 1H), 4.04 (d, J = 4.5 Hz, 1H), 3.03-2.93 (m, 1H),2.90-2.79 (m, 1H), 2.70 (ddd, J = 5.8, 9.1, 15.5 Hz, 1H), 2.64 (s, 3H),2.34-2.22 (m, 1H), 2.15-1.81 (m, 2H), 1.76-1.65 (m, 1H)

364 [M − NH₂] (1S,2S,3S,5R)-3-(((R)-3-amino-2,3-dihydro-1H-inden-4-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 1H),7.70 (d, J = 3.5 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.86- 6.75 (m, 2H),6.69 (s, 1H), 5.37 (br. s, 1H), 5.23-5.03 (m, 2H), 4.66- 4.55 (m, 2H),4.48 (dd, J = 4.5, 7.5 Hz, 1H), 4.02 (d, J = 4.3 Hz, 1H), 3.02-2.93 (m,1H), 2.90-2.80 (m, 1H), 2.76-2.66 (m, 1H), 2.66-2.59 (m, 3H), 2.28 (dt,J = 8.2, 13.6 Hz, 1H), 2.06-1.97 (m, 1H), 1.77-1.64 (m, 1H)

Example 143 (SchemeYY)—(1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chloro-3-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (YY-6)

Step 1—Synthesis of 3-chloro-2-fluoro-6-methoxybenzaldehyde (YY-2)

To a solution of 4-chloro-3-fluoroanisole (YY-1) (250 mg, 1.56 mmol) inanhydrous THF was added LDA (0.86 mL, 2M, 1.71 mmol) drop-wise under N₂,at −78° C. and stirred at −78° C. for 30 min under N₂. To the abovesolution was added DMF (125 mg, 1.71 mmol) at −78° C. under N₂ and theresulting mixture was stirred at −78° C. for 20 min. The reaction wasquenched by sat. NH₄Cl at −78° C. The resulting mixture was warmed to25° C. The mixture was partitioned between EtOAc and H₂O. The organiclayer was separated and the aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to afford the crude product. The crude product was purifiedvia flash column (EtOAc:petroleum ether=1%-12%) to afford YY-2 (178 mg,61%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.41 (d, J=1.3 Hz,1H), 7.54 (dd, J=8.0, 9.0 Hz, 1H), 6.76 (dd, J=1.5, 9.0 Hz, 1H), 3.95(s, 3H)

Step 2—Synthesis of (3-chloro-2-fluoro-6-methoxyphenyl)methanamine(YY-3)

To a solution of YY-2 (400 mg, 2.12 mmol) in anhydrous MeOH (20.0 mL)was added NH₄OAc (1.63 g, 21.2 mmol). The mixture was stirred at 25° C.for 1 hour. To the above solution was added NaCNBH₃ (533 mg, 8.48 mmol)at 25° C. The resulting mixture was stirred for 16 hours at 25° C. Thereaction mixture was partitioned between EtOAc and H₂O. The organiclayer was separated, washed with brine, dried over Na₂SO₄ andconcentrated to afford the crude product which was purified via flashcolumn (MeOH:DCM=1%-15%) to afford YY-3 (270 mg, 67%) as a yellow gum.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.35 (t, J=8.8 Hz, 1H), 6.78 (d, J=9.0Hz, 1H), 3.77 (s, 3H), 3.70 (s, 2H)

Step 3—Synthesis of 2-(aminomethyl)-4-chloro-3-fluorophenol (YY-4)

To a solution of YY-3 (180 mg, 0.949 mmol) in H₂O (15.0 mL) was addedaq.HBr (1.50 mL) drop-wise at 0° C. under N₂. After the addition, thereaction was heated at reflux (110° C.) and stirred for 6 hours. Thereaction mixture was cooled to 0° C., diluted in H₂O, and neutralizedwith sat. NaOH. The aqueous layer was extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated toafford the crude product which was purified via pre-TLC (MeOH:DCM=1:10)to afford YY-4 (50 mg, 30%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.18 (t, J=8.9 Hz, 1H), 6.52 (dd, J=1.5, 8.8 Hz, 1H), 3.92 (d, J=1.3Hz, 2H)

Step 4—Synthesis of tert-butyl(3-chloro-2-fluoro-6-hydroxybenzyl)carbamate (YY-5)

To a solution of YY-4 (50.0 mg, 0.285 mmol) in DCM (5.00 mL) and MeOH(1.0 mL) was added Boc₂O (68.4 mg, 0.313 mmol) followed by Et₃N (72 mg,0.71 mmol) at 0° C. After the addition, the reaction mixture was stirredat 25° C. for 16 hours. The reaction mixture was acidified by sat.citric acid to pH 5-6. The mixture was partitioned between DCM and H₂O.The organic layer was separated and the aqueous layer was extracted withDCM. The combined organic layer was washed with sat.NaHCO₃ and brine,dried over Na₂SO₄ and concentrated to afford the crude product which waspurified via pre-TLC (EtOAc:Petroleum ether=1:2) to afford YY-5 (45 mg,57%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.22 (s, 1H),7.27 (t, J=8.4 Hz), 7.02 (br. s, 1H), 6.67 (d, J=9.2 Hz), 4.14 (s, 2H),1.37 (s, 9H)

Step 5—Synthesis of(1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chloro-3-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(YY-6)

Compound YY-6 was synthesized using YY-5 and BB-2 following proceduressteps 2 & 3 in Scheme BB.

LCMS 407 [M+1]; ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ ppm 8.57 (s, 1H), 7.61(d, J=3.5 Hz, 1H), 7.56 (t, J=8.7 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 6.72(br. s., 1H), 5.14-4.99 (m, 1H), 4.64 (br. s., 1H), 4.59 (dd, J=4.6, 9.4Hz, 1H), 4.08 (s, 3H), 2.90-2.78 (m, 1H), 2.62 (s, 3H), 2.06 (t, J=10.4Hz, 1H)

Example 144-146 were made in a similar fashion as YY-6 starting with theappropriate anisole reagent and following steps 3 & 4 in Scheme YY.

423 [M + 1] (1S,2S,3S,5R)-3-(2-(aminomethyl)-3-(trifluoromethyl)phenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm = 8.60 (s, 1H), 7.71 (d, J = 3.5 Hz, 1H), 7.56-7.48 (m,1H), 7.47-7.40 (m, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 3.5 Hz,1H), 5.11 (q, J = 9.3 Hz, 1H), 4.71 (br. s., 1H), 4.65 (dd, J = 4.9, 9.2Hz, 1H), 4.13 (d, J = 4.3 Hz, 1H), 4.02 (br. s., 2H), 2.97-2.82 (m, 1H),2.64 (s, 3H), 2.11 (ddd, J = 4.3, 9.7, 13.7 Hz, 1H)

391 [M + 1] (1S,2S,3S,5R)-3-(2-(aminomethyl)-3,4-difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.61 (s, 1H), 7.68 (s, 1H), 7.31-7.20 (m, 1H), 6.90-6.83 (m, 1H), 6.72(d, J = 3.5 Hz, 1H), 5.54-5.25 (m, 1H), 5.17-5.03 (m, 2H), 4.68-4.55 (m,2H), 4.07-4.01 (m, 1H), 3.77 (d, J = 1.3 Hz, 2H), 2.90- 2.79 (m, 1H),2.64 (s, 3H), 2.10-1.99 (m, 1H)

403 [M + 1] (1S,2S,3S,5R)-3-(2-(2-aminoethyl)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆ + D₂O) δppm 8.59 (s, 1H), 7.58 (d, J = 3.8 Hz, 1H), 7.23-7.16 (m, 2H), 7.00 (d,J = 8.5 Hz, 1H), 6.72 (d, J = 3.8 Hz, 1H), 5.16-5.01 (m, 1H), 4.62-4.46(m, 2H), 3.99 (d, J = 5.3 Hz, 1H), 2.91-2.81 (m, 1H), 2.79- 2.68 (m,2H), 2.62 (s, 2H), 2.00-1.88 (m, 1H)

Example 147 (SchemeZZ)—(1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-dichlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(ZZ-7)

Step 1—Synthesis of (4,5-dichloro-2-methoxyphenyl)methanol (ZZ-2)

To a solution of methoxybenzoic acid (ZZ-1) (500 mg, 2.26 mmol) inanhydrous THF (23 mL) was added BH₃.THF (6.79 mL, 6.79 mmol) at 0° C.under N₂. After the addition, the reaction mixture was stirred at 30° C.under N₂ for 3 hours. The reaction mixture was cooled to −20° C. andquenched with sat. NH₄Cl. The reaction mixture was partitioned betweenEtOAc and H₂O. The organic layer was separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to afford the crude productwhich was purified via flash column chromatography (EtOAc:Petroleumether=1%-35%) to afford the ZZ-2 (383 mg, 81.8%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.49 (s, 1H), 7.22 (s, 1H), 5.28 (t, J=5.6Hz), 4.44 (d, J=6 Hz), 3.31 (s, 3H)

Step 2—Synthesis of2-(4,5-dichloro-2-methoxybenzyl)isoindoline-1,3-dione (ZZ-3)

To a solution of ZZ-2 (230 mg, 1.11 mmol) and phthalimide (163 mg, 1.11mmol) in anhydrous THF (12 mL) was added PPh₃ (291 mg, 2.30 mmol). Thereaction mixture was stirred at −20° C. under N₂ for 30 min. To theabove solution was added DEAD (193 mg, 1.11 mmol) at −10° C.˜-20° C.After the addition, the reaction mixture was became a yellow solution,which was warmed to 25° C. and stirred for 2 hours. The reaction mixturewas concentrated and the residue was purified via flash column (12.0 ggel, EtOAc:petroleum Ether=10%-35%) to afford the crude product andfurther purified via prep-TLC (EtOAc:petroleum=1%˜15%) to afford theproduct ZZ-3 (30 mg, 8%) as a white solid and used as is in the nextstep.

Step 3—Synthesis of2-(4,5-dichloro-2-hydroxybenzyl)isoindoline-1,3-dione (ZZ-4)

To a solution of ZZ-3 (50 mg, 0.15 mmol) in DCM (2.00 mL) was added BBr₃(0.20 mL) dropwise at 0° C. After the addition, the reaction was stirredat 0° C. for 2 hours. The reaction mixture was quenched with MeOHcarefully. The resulting mixture was partitioned between DCM and sat.NaHCO₃. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to afford the crude product which was purified via prep-TLC(EtOAc:petroleum ether=1:1) to afford ZZ-4 (43 mg, 90%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (s, 1H), 7.94-7.76 (m, 4H),7.32 (s, 1H), 7.00 (s, 1H), 4.68 (s, 2H)

Step 4—Synthesis of2-(4,5-dichloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)benzyl)isoindoline-1,3-dione(ZZ-5)

To a stirred solution of ZZ-4 (43 mg, 0.13 mmol) and tert-butyl((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl) carbonate (42 mg, 0.13 mmol)in DCE (1.50 mL) was added Cs₂CO₃ (52 mg, 0.16 mmol), Pd₂(dba)₃.CHCl₃,(3.5 mg, 0.003 mmol) and dppp (3.3 mg, 0.008 mmol). The reaction mixturewas degassed and purged with N₂ for 3 times. The resulting solution wasstirred for 1.5 hrs at 25° C. The reaction mixture was concentrated andpurified via prep-TLC (EtOAc:petroleum ether=1:1) to afford the productZZ-5 (62 mg, 89%) as a yellow gum and used in the next step directly.

Step 5—Synthesis of2-(4,5-dichloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)isoindoline-1,3-dione(ZZ-6)

To a solution of ZZ-5 (62 mg, 0.12 mmol) in THF (2.50 mL) and H₂O (0.50mL) was added NMO (29.4 mg, 0.251 mmol) followed by OsO₄ (136 mg, 0.02mmol, 4% w/w in t-BuOH). After the addition, the reaction mixture wasstirred at 28° C. for 4 hours. The reaction mixture was diluted in H₂Oand quenched with sat. NaHSO₃. The dark solution was extracted withEtOAc, dried over Na₂SO₄ and concentrated to afford the crude productwhich was purified via prep-TLC (MeOH:DCM=1:10, UV) to afford ZZ-6 (30mg, 45%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (s,1H), 7.95-7.77 (m, 4H), 7.60 (d, J=3.5 Hz, 1H), 7.56 (s, 1H), 7.36 (s,1H), 6.73 (d, J=3.5 Hz, 1H), 5.43 (d, J=4.0 Hz, 1H), 5.18-5.05 (m, 2H),4.81 (s, 2H), 4.70-4.61 (m, J=6.0 Hz, 1H), 4.52-4.41 (m, 1H), 3.99-3.94(m, 1H), 2.91-2.78 (m, 1H), 2.65 (s, 3H), 1.98-1.86 (m, 1H)

Step 6—Synthesis of(1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-dichlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(ZZ-7)

To a solution of ZZ-6 (30 mg, 0.05 mmol) in THF (2.5 mL) was addedNH₂NH₂ (31 mg, 0.81 mmol) drop-wise. After the addition, the reactionsolution was stirred at 28° C. for 16 hours. The reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified viaprep-HPLC to afford ZZ-7 (11 mg, 46%) as a white solid. LCMS 423 [M+1];¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1H), 7.66 (d, J=3.8 Hz, 1H),7.60 (s, 1H), 7.31 (s, 1H), 6.72 (d, J=3.3 Hz, 1H), 5.14-5.05 (m, 2H),4.63 (m, 1H), 4.00 (m, 1H), 3.74 (s, 2H), 2.89-2.81 (m, 1H), 2.64 (s,3H), 2.02 (m, 1H)

Example 148(1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol was prepared in a similarfashion to ZZ-7 starting with (4,5-difluoro-2-methoxyphenyl)methanol andfollowing steps 2 through 6 in Scheme ZZ.

391 [M + 1] (1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.62 (s, 1H), 7.75-7.57 (m, 1H), 7.51-7.32 (m, 1H), 7.25-7.05 (m, 1H),6.72 (d, J = 3.5 Hz, 1H), 5.39 (d, J = 18.1 Hz, 1H), 5.20-4.98 (m, 2H),4.57 (d, J = 4.8 Hz, 2H), 4.01 (d, J = 4.3 Hz, 1H), 3.72 (s, 2H),2.95-2.72 (m, 1H), 2.62 (s, 3H), 2.00 (ddd, J = 4.5, 9.1, 13.7 Hz, 1H)

Example 149 (SchemeAAA)—(1S,2S,3S,5R)-3-(2-(2-amino-1-hydroxyethyl)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(AAA-9)

Step 1—Synthesis of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethan-1-one(AAA-2)

To a yellow solution of 1-(5-chloro-2-hydroxyphenyl)ethan-1-one (AAA-1)(2 g, 11.72 mmol) and in THF (60 mL) was added PhMe₃NBr₃ (4.85 g, 12.9mmol) at rt (25° C.). The resulting red solution was stirred at rt for12 hrs in which solid was formed, then the mixture was filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel chromatography eluted with EtOAc in petroleum ether from 0 to10% to AAA-2 (2.4 g) as a yellow oil which was used in the next stepdirectly.

Step 2—Synthesis of2-((3r,5r,7r)-1I4,3,5,7-tetraazaadamantan-1-yl)-1-(5-chloro-2-hydroxyphenyl)ethan-1-one,bromide salt (AAA-3)

To a solution of 1,3,5,7-tetraazaadamantane (4.67 g, 33.3 mmol) in CHCl₃(40 mL) was added to AAA-2 (2.6 g, 10 mmol) at rt (25° C.). The mixturewas stirred at rt for 12 hrs in which solid was formed. The solid wascollected by filtration and rinsed with DCM and dried in vacuo to affordcrude AAA-3 (3 g, 74%) as a white solid, used in the next step directly.

Step 3—Synthesis of 2-amino-1-(5-chloro-2-hydroxyphenyl)ethan-1-one(AAA-4)

To a suspension of SM1 (3 g, 8 mmol) in EtOH (15 mL) was added conc. HCl(3 mL) at rt (25° C.). The suspension was stirred at rt for 2 hrs. Thereaction was evaporated to give AAA-4 (1.5 g, >100%) as yellow oil whichwas used directly without further purification. LCMS 186 [M+1]

Step 4—Synthesis of tert-butyl(2-(5-chloro-2-hydroxyphenyl)-2-oxoethyl)carbamate (AAA-5)

To a solution of (Boc)₂O (2.29 g, 10.5 mmol) in dioxane (15 mL) wasadded the solution of AAA-4 (200 mg, solution, neutralized by NaHCO₃aq.) at 0° C. The reaction solution was stirred at 25° C. The reactionsolution was extracted with EtOAc (6 mL×3). The organic layers wereseparated, dried and evaporated to give the crude product which waspurified by flash chromatography with 0-25% EtOAc/petroleum ether, togive AAA-5 (600 mg, 22%) as a white solid and used as is in the nextstep.

Step 5—Synthesis of tert-butyl(2-(5-chloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)phenyl)-2-oxoethyl)carbamate(AAA-6)

Using BB-2 and following similar procedures as step 2 in Scheme BB,AAA-6 was obtained (288 mg, 31%) as a yellow gum and used in the nextstep directly.

Step 6—Synthesis of tert-butyl(2-(5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl)-2-oxoethyl)carbamate(AAA-7)

Starting with AAA-6 and following similar procedures as step 3 in SchemeBB, AAA-7 was obtained (70 mg, 33%) as a white solid. LCMS 517 [M+1]

Step 7—Synthesis of tert-butyl(2-(5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl)-2-hydroxyethyl)carbamate(AAA-8)

To a mixture of AAA-7 (70 mg, 0.14 mmol) in MeOH (1 mL) was added NaBH₄(15.4 mg, 0.406 mmol). The mixture was stirred at 25° C. for 2 h. Themixture was quenched by 1N HCl aq. (5 mL). The mixture was evaporated togive the crude product AAA-8 (70 mg, >99%) as a white solid.

Step 8—Synthesis of(1S,2S,3S,5R)-3-(2-(2-amino-1-hydroxyethyl)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(AAA-9)

Compound AAA-8 (62 mg, 0.12 mmol) was dissolved in DCM (0.6 mL). Themixture was cooled to 0° C. in an ice bath. TFA (0.2 mL) was added tothe above mixture drop-wise. The reaction mixture was stirred at 25° C.for 2 hours. The reaction solution was neutralized by saturated NaHCO₃aq. (1 mL), filtered and the filtrate was purified by prep-HPLC directlyto give AAA-9 (21 mg, 42%) as a white solid. LCMS 441 [M+23]; ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.62 (d, J=2.8 Hz, 1H), 7.58 (dd, J=3.3, 11.3Hz, 1H), 7.48 (s, 1H), 7.26-7.22 (m, 1H), 7.03 (dd, J=2.1, 8.7 Hz, 1H),6.75 (t, J=3.8 Hz, 1H), 5.20 (d, J=3.8 Hz, 1H), 5.10 (br. s., 1H), 4.70(br. s., 2H), 4.22 (d, J=9.5 Hz, 1H), 3.04-2.94 (m, 2H), 2.77 (br. s.,1H), 2.71 (s, 3H), 2.26 (br. s., 1H)

Example 150 (SchemeBBB)—(1S,2S,3S,5R)-3-(2-(aminomethyl)-3,4-dichlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(BBB-8)

Step 1—Synthesis of 2,3-dichloro-6-fluorobenzaldehyde (BBB-2)

To a solution of 1,2-dichloro-4-fluorobenzene (BBB-1) (2 g, 12.12 mmol)in anhydrous THF (30 mL) was added LDA (6.67 mL, 2M, 13.3 mmol)drop-wise under N₂, at −65° C. After the addition, the reaction mixturewas stirred at −65° C. for 30 min under N₂. To the resulting redsolution was added DMF (1.77 g, 24.2 mmol) at −65° C. under N₂ and theresulting mixture was stirred at −65° C. for 20 min. The reaction wasquenched with water (50 mL) and extracted with EtOAc (30 mL×2). Theextract was washed with 1 N HCl (30 mL), brine (30 mL), dried overNa₂SO₄ and concentrated to give the crude material which was extractedwith petroleum ether (30 mL×3). The extract was concentrated in vacuo toafford BBB-2 (2.2 g, 94%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δppm 10.44 (s, 1H), 7.66 (dd, J=5.3, 9.0 Hz, 1H), 7.10 (t, J=9.2 Hz, 1H)

Step 2—Synthesis of 2,3-dichloro-6-hydroxybenzaldehyde (BBB-3)

To a yellow solution of crude BBB-2 (2.2 g, 11.4 mmol) in DMSO (10 mL)was added KOH (1280 mg, 22.8 mmol) slowly at 0° C. After addition, themixture was changed into red mixture and stirred at room temperature(20° C.) for 16 hrs. The mixture was diluted with MTBE (100 mL). Theliquid was decanted out and residue was washed with MTBE (100 mL). Theresidue was then diluted with water (30 mL) and adjusted with 1 N HCl topH 2 and extracted with EtOAc (20 mL×2). The extract was washed withbrine (20 mL), dried over Na₂SO₄ and concentrated in vacuo to affordcrude BBB-3 (390 mg, 18%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm11.98 (s, 1H), 10.44 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 6.90 (d, J=9.3 Hz,1H)

Step 3—Synthesis of(R,E)-N-(2,3-dichloro-6-hydroxybenzylidene)-2-methylpropane-2-sulfinamide(4)

A mixture of crude BBB-3 (150 mg, 0.79 mmol),(R)-2-methylpropane-2-sulfinamide (143 mg, 1.2 mmol) and CuSO₄ (376 mg,2.36 mmol) in CHCl₃ (3 mL) was stirred at rt (30° C.) for 5 days. Themixture was filtered and purified by silica gel chromatography elutedwith EtOAc in petroleum ether from 0 to 30% to afford BBB-4 (70 mg, 30%)as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 11.98 (s, 1H),9.28 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 6.92 (d, J=9.3 Hz, 1H), 1.29 (s,9H)

Step 4—Synthesis of(R)—N-(2,3-dichloro-6-hydroxybenzyl)-2-methylpropane-2-sulfinamide(BBB-5)

To a solution of BBB-4 (70 mg, 0.238 mmol) in MeOH (3 mL) was addedNaBH₄ (27 mg, 0.714 mol) at rt (30° C.). The mixture was stirred at rtfor 1 h. The mixture was concentrated in vacuo and dissolved in water (5mL). To the mixture was added NH₄Cl aq (2 mL) in which some solid wasformed. The mixture was extracted with EtOAc (5 mL×3). The extract waswashed with brine (5 mL), dried over Na₂SO₄ and concentrated in vacuo toafford BBB-5 (55 mg, 78%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δppm 9.31 (br. s., 1H), 7.17 (d, J=8.8 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H),4.58-4.40 (m, 2H), 4.09-3.97 (m, 1H), 1.27 (s, 9H)

Step 5—Synthesis of(R)—N-(2,3-dichloro-6-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)benzyl)-2-methylpropane-2-sulfinamide(BBB-6)

Compound BBB-6 (130 mg, 98%, containing 1 eq of DCM) was prepared as ayellow gum from BBB-5 and BB-2 using similar procedures to step 2 ofScheme BB. LCMS 493 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H),7.39-7.31 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 6.60 (d, J=3.5 Hz, 1H), 6.41(d, J=5.5 Hz, 1H), 6.22 (d, J=4.8 Hz, 1H), 6.13-6.01 (m, 1H), 5.41-5.35(m, 1H), 4.63-4.39 (m, 2H), 3.65 (t, J=6.7 Hz, 1H), 3.29-3.09 (m, 1H),2.73 (s, 3H), 1.98 (td, J=3.8, 14.7 Hz, 1H), 1.18 (s, 9H)

Step 6—Synthesis ofN-(2,3-dichloro-6-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)-2-methylpropane-2-sulfonamide(BBB-7)

Compound BBB-6 was treated in a similar fashion to procedures of step 3in scheme BB to afford BBB-7 (70 mg, 58%). LCMS 543 [M+16+1]; ¹H NMR(400 MHz, CDCl₃) δ ppm 8.62 (s, 1H), 7.56 (br. s., 1H), 7.19 (d, J=8.8Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.54 (d, J=3.8 Hz, 1H), 5.64 (t, J=5.5Hz, 1H), 5.14 (s, 1H), 5.13-5.04 (m, 1H), 4.56-4.50 (m, 1H), 4.47 (dd,J=4.8, 8.5 Hz, 1H), 4.44-4.34 (m, 2H), 4.04 (d, J=4.8 Hz, 1H), 2.83-2.75(m, 1H), 2.62 (s, 3H), 2.14-2.04 (m, 1H), 1.20 (s, 9H)

Step 7—Synthesis of(1S,2S,3S,5R)-3-(2-(aminomethyl)-3,4-dichlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(BBB-8)

To a solution of BBB-7 (35 mg, 0.064 mmol) in dry DCM (5 mL) was addedanisole (170 mg, 1.56 mmol) and AlCl₃ (86 mg, 0.64 mmol) at rt (25° C.).The white suspension was stirred at rt for 3 h. The mixture was quenchedwith NaHCO₃ aq (3 mL), followed by potassium sodium tartrate aq (5 mL).The mixture was extracted with EtOAc (5 mL×3). The extract wasconcentrated in vacuo and purified by TLC (DCM/MeOH=10/1) to affordBBB-8 (8 mg, 29%) as a white solid. LCMS 423 [M+1]; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.61 (s, 1H), 7.69 (d, J=3.5 Hz, 1H), 7.49 (d, J=8.8 Hz,1H), 7.11 (d, J=9.0 Hz, 1H), 6.72 (d, J=3.8 Hz, 1H), 5.44 (br. s., 1H),5.10 (q, J=9.0 Hz, 2H), 4.64 (d, J=5.3 Hz, 2H), 4.06 (d, J=4.8 Hz, 1H),3.92 (s, 2H), 2.92-2.81 (m, 1H), 2.64 (s, 3H), 2.05 (ddd, J=4.1, 9.2,13.8 Hz, 1H)

Example 151 (SchemeCCC)—(1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-dichlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(CCC-4)

Step 1—Synthesis of4,5-dichloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)phenol(CCC-1)

Compound CCC-1 was prepared using similar procedures to step 2 in schemeBB with commercially available 4,5-dichlorobenzene-1,2-diol and BB-2.

Step 2—Synthesis of tert-butyl(2-(4,5-dichloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)phenoxy)ethyl)carbamate(CCC-2)

To a stirred yellow solution of CCC-1 (78 mg, 0.21 mmol) in dry DMF (5mL) was added K₂CO₃ (86 mg, 0.62 mmol) and tert-butyl(2-bromoethyl)carbamate (923 mg, 0.42 mmol) at 25° C. and stirred for 20hours. Water (10 mL) was added to the reaction mixture and extractedwith EtOAc (2×20 mL). The combined organic layers were washed with brine(5×20 mL), dried over Na₂SO₄, filtered and concentrated in vacuum togive the residue which was purified by column chromatography (silicagel, eluted with EtOAc) to give CCC-2 (108 mg, >99%) as a colorless gum.LCMS [M+1] 519; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H), 7.42 (d,J=3.5 Hz, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 6.60 (d, J=3.5 Hz, 1H), 6.39(td, J=1.9, 5.5 Hz, 1H), 6.19 (dd, J=2.3, 5.3 Hz, 1H), 6.06 (dd, J=2.0,4.8 Hz, 1H), 5.29 (d, J=7.0 Hz, 1H), 5.02 (br. s., 1H), 4.03 (t, J=5.0Hz, 2H), 3.59-3.47 (m, 2H), 3.10 (td, J=7.7, 15.2 Hz, 1H), 2.73 (s, 3H),2.07 (t, J=2.9 Hz, 1H), 1.42 (s, 9H)

Step 3—Synthesis of tert-butyl(2-(4,5-dichloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenoxy)ethyl)carbamate(CCC-3)

Compound CCC-2 was subjected to similar procedures as step 3 in SchemeBB to afford CCC-3 (55 mg, 48%) as brown gum. LCMS [M+23] 575

Step 4—Synthesis of(1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-dichlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(CCC-4)

Compound CCC-3 was subjected to standard TFA/water deprotection methodssimilar to step 8 in scheme AAA followed by prep-HPLC to afford CCC-4(35 mg, 75%). LCMS [M+23] 475; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.64 (s,1H), 7.66 (d, J=3.8 Hz, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 6.79 (d, J=3.5Hz, 1H), 5.20 (q, J=8.9 Hz, 1H), 4.76-4.68 (m, 1H), 4.66 (dd, J=5.3, 8.0Hz, 1H), 4.33-4.23 (m, 3H), 3.40-3.36 (m, 2H), 3.01-2.90 (m, 1H), 2.74(s, 3H), 2.29 (ddd, J=5.0, 8.8, 14.3 Hz, 1H)

Example 152(1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol was prepared in a similarfashion to CCC-4 starting with 4,5-difluorobenzene-1,2-diol andfollowing steps 1 through 4 in Scheme CCC.

421 [M + 1] (1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.64 (s, 1H), 7.67 (d, J = 3.5 Hz, 1H), 7.26-7.07 (m,2H), 6.80 (d, J = 4.0 Hz, 1H), 5.19 (q, J = 8.9 Hz, 1H), 4.72-4.64 (m,2H), 4.33- 4.21 (m, 3H), 3.42-3.36 (m, 2H), 2.99- 2.87 (m, 1H), 2.75 (s,3H), 2.33-2.23 (m, 1H)

Example 153 (SchemeDDD)—(1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(DDD-6)

Step 1—Synthesis of1-(5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl)ethan-1-one (DDD-1)

Compound DDD-1 was prepared using similar procedures to steps 2 & 3 inscheme BB with commercially available1-(5-chloro-2-hydroxyphenyl)ethan-1-one and BB-2.

Step 2—Synthesis of5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl acetate (DDD-2)

Trifluoroacetic anhydride (1.46 g, 6.95 mmol) cooled to −10° C. wasadded dropwise and 30% H₂O₂(185 mg, 1.63 mmol) and the solution wasstirred for 10 min. To this mixture was added DDD-1 (210 mg, 0.523 mmol)in DCM (3.5 mL) dropwise at 0° C. and stirred at 25° C. for 15 min. Thensaturated sodium thiosulfate (2 mL) was added to the reaction solution.The reaction solution was basified by saturated NaHCO₃ to pH=7˜8,extracted with DCM (30 mL×2). The combined organic layers were washedwith brine (40 mL), dried over Na₂SO₄, filtered and evaporated to givecrude material, which was purified by ISCO (silica gel, 12 g,MeOH/DCM=10%˜14%) to give desired product DDD-2 (160 mg, 73%) as a whitesolid. LCMS [M+1] 418; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.67 (s, 1H), 7.25(m, 1H), 7.21 (dd, J=2.5, 8.8 Hz, 1H), 7.12-7.06 (m, 2H), 6.60 (d, J=3.8Hz, 1H), 4.97 (q, J=8.5 Hz, 1H), 4.78 (t, J=6.0 Hz, 1H), 4.50 (dd,J=5.3, 8.3 Hz, 1H), 4.29 (d, J=5.5 Hz, 1H), 3.12-3.01 (m, 1H), 2.72 (s,3H), 2.36-2.27 (m, 1H), 2.24 (s, 3H)

Step 2—Synthesis of5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenylacetate (DDD-3)

To a stirred colorless solution of DDD-2 (160 mg, 0.38 mmol) in acetone(0.64 mL) was added 2,2-dimethoxypropane (6.4 mL) and p-toluenesulfonicacid (73 mg, 0.38 mmol) at 25° C. The reaction was stirred at 25° C. for1 hour. Then aq.NaHCO3 (3 mL) was added to the reaction mixture untilthe pH 8.0. Then the mixture was extracted with EtOAc (15 mL×2). Theorganic layers were separated, washed with brine (20 mL), dried overNa₂SO₄ and filtered. The organic layer was evaporated to give the crudeproduct as a colorless gum, which was purified by column chromatography(ether:EtOAc=1:1, Rf˜0.55) to give the DDD-3 (126 mg, 72%) as a whitesolid. LCMS [M+1] 458; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.79 (s, 1H), 7.43(d, J=3.8 Hz, 1H), 7.25-7.20 (m, 1H), 7.14-7.07 (m, 2H), 6.58 (d, J=3.5Hz, 1H), 5.46-5.38 (m, 1H), 4.93 (d, J=5.8 Hz, 1H), 4.83-4.74 (m, 2H),3.06-2.89 (m, 1H), 2.74 (s, 3H), 2.52-2.37 (m, 1H), 2.21 (s, 3H), 1.60(br. s., 3H), 1.32 (s, 3H)

Step 3—Synthesis of5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenol(DDD-4)

Compound DDD-3 (142 mg, 0.31 mmol) was dissolved in MeOH (3 mL) and H₂O(1 mL). K₂CO₃ (85.7 g, 0.62 mmol) was added to the above mixture. Thereaction mixture was stirred at 25° C. for 1 hour. The mixture wasneutralized with 10% citric acid to pH 6-7. The mixture was diluted withH₂O (10 mL), extracted by EtOAc (10 mL×2). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andevaporated to give DDD-4 (140 mg, >99%) as a colorless gum. LCMS [M+1]416; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.79 (s, 1H), 7.22 (d, J=3.5 Hz, 1H),6.96-6.90 (m, 2H), 6.87-6.81 (m, 1H), 6.61 (d, J=3.5 Hz, 1H), 5.95-5.74(m, 1H), 5.27-5.19 (m, 2H), 4.87-4.78 (m, 2H), 2.99-2.87 (m, 1H), 2.74(s, 3H), 2.61-2.50 (m, 1H), 1.59 (s, 3H), 1.34 (s, 3H)

Step 4—Synthesis of tert-butyl(2-(5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenoxy)ethyl)carbamate(DDD-5)

To a stirred solution of DDD-4 (140 mg, 0.34 mmol) in dry DMF (5 mL) wasadded K₂CO₃ (140 mg, 1.0 mmol) and tert-butyl (2-bromoethyl)carbamate(151 mg, 0.67 mmol) at 25° C. The reaction was stirred at 25° C. for 15hours. Water (10 mL) was added to the reaction mixture and the mixturewas extracted with EtOAc (20 mL×2). The combined organic layers werewashed with brine (20 mL×5), dried over Na₂SO₄, filtered andconcentrated to give crude material which was purified by ISCO(EtOAc/petroleum ether=60%) to give DDD-5 (170 mg, 90%) as a colorlessgum. LCMS [M+23] 581; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.80 (s, 1H), 7.77(d, J=3.8 Hz, 1H), 6.96-6.84 (m, 3H), 6.59 (d, J=3.8 Hz, 1H), 5.50 (d,J=8.0 Hz, 1H), 5.18 (br. s., 1H), 4.92-4.86 (m, 1H), 4.85-4.81 (m, 2H),4.08-3.98 (m, 2H), 3.65-3.54 (m, 2H), 3.08-2.98 (m, 1H), 2.74 (s, 3H),2.47 (d, J=14.6 Hz, 1H), 1.59 (s, 3H), 1.42 (s, 9H), 1.31 (s, 3H)

Step 5—Synthesis of(1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(DDD-6)

Compound DDD-5 was subjected to standard TFA/water deprotection methodsfollowed by prep-HPLC to afford DDD-6 (40 mg, 31%). LCMS [M+23] 441; ¹HNMR (400 MHz, MeOD-d₄) 5 ppm 8.64 (s, 1H), 7.78 (d, J=3.8 Hz, 1H),7.14-7.05 (m, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.82 (d, J=3.8 Hz, 1H),5.41-5.27 (m, 1H), 4.74-4.70 (m, J=5.5 Hz, 1H), 4.67 (dd, J=4.6, 7.9 Hz,1H), 4.21 (d, J=4.5 Hz, 1H), 4.15-4.07 (m, 2H), 3.18-3.08 (m, 2H),3.06-2.94 (m, 1H), 2.74 (s, 3H), 2.14 (dd, J=6.8, 14.1 Hz, 1H)

(Scheme EEE)—Synthesis of tert-butyl5-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-19)

Step 1—Synthesis of (2-chloro-5-methoxyphenyl)methanol (EEE-2)

To a solution of methyl 2-chloro-5-methoxybenzoate EEE-1 (4.55 g, 22.7mmol) in anhydrous THF (200 mL) was added LiAlH₄ (1.72 g, 45.4 mmol) at−10° C.˜-5° C. portion-wise. The temperature was raised to 0° C. Afterthe addition, the reaction was stirred at 0° C. for 2 hours. Thereaction mixture was quenched by 5% NaOH. The reaction mixture wasfiltered through a pad of Celite. To the Celite cake was added THF (100mL) and EtOAc (100 mL) and stirred sat 25° C. for 0.5 hour. The mixturewas filtered and the combined organic layers were dried over Na₂SO₄ andconcentrated to afford the crude EEE-2 (4.5 g) as a colorless oil andused directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.25 (d,J=9.5 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 6.78 (dd, J=2.9, 8.7 Hz, 1H),4.75 (d, J=3.8 Hz, 2H), 3.81 (s, 3H), 2.04-1.94 (m, 1H)

Step 2—Synthesis of 2-chloro-5-methoxybenzaldehyde (EEE-3)

To a solution of EEE-2 (3.63 g, 16.16 mmol) in CH₃CN (120 mL) was addedIBX (17.7 g, 63.1 mmol) at 25° C. The resulting mixture was heated at80° C. for 2 hours. The reaction mixture was cooled to 25° C., filtered,and washed with DCM (50 mL). The combined filtrate was concentrated toafford crude material which was purified by ISCO (silica gel, 80 g,EtOAc/petroleum ether=17%) to EEE-3 (1.76 g, 49%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 10.45 (s, 1H), 7.42 (d, J=3.0 Hz, 1H), 7.36(d, J=8.8 Hz, 1H), 7.11 (dd, J=3.3, 8.8 Hz, 1H), 3.86 (s, 3H)

Step 3—Synthesis of (E)-1-chloro-4-methoxy-2-(2-nitrovinyl)benzene(EEE-4)

To a solution of EEE-3 (1.76 g, 10.3 mmol) in AcOH (17.0 mL) was addedNH₄OAc (0.795 g, 10.3 mmol) followed by MeNO₂ (3.15 g, 51.6 mmol). Afterthe addition, the reaction mixture was heated at 85° C. for 10 hours,and then cooled to 28° C. The reaction was diluted in DCM andconcentrated to remove AcOH to afford the crude product which waspurified via flash column (12 g gel, EtOAc:Petroleum ether=1%˜10%) toafford EEE-4 (1.78 g, 81%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δppm 8.36 (d, J=13.8 Hz, 1H), 7.58 (d, J=13.8 Hz, 1H), 7.39 (d, J=9.0 Hz,1H), 7.05 (d, J=3.0 Hz, 1H), 6.99 (dd, J=3.0, 9.0 Hz, 1H), 3.85 (s, 3H)

Step 4—Synthesis of 2-(2-chloro-5-methoxyphenyl)ethan-1-amine (EEE-5)

To a solution of EEE-4 (862 mg, 4.04 mmol) in anhydrous THF (40 mL) wasadded LiAlH₄ (613 mg, 16.1 mmol) at −20° C. under N₂. After theaddition, the reaction mixture was stirred at 25° C. for 1 hour. Thereaction mixture was then heated at 50° C. and stirred for 2 hours. Thereaction mixture was quenched with drops of water. The reaction mixturewas diluted with EtOAx, filtered, and concentrated to afford the crudeproduct which was purified via flash column chromatography (40 g gel,MeOH:DCM=1%-8.0%) to afford EEE-5 (290 mg, 38.7%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.27-7.24 (m, 1H), 6.79 (d, J=2.8 Hz, 1H),6.72 (dd, J=3.0, 8.8 Hz, 1H), 3.79 (s, 3H), 3.02-2.95 (m, 2H), 2.90-2.80(m, 2H)

Step 5—Synthesis of 5-chloro-8-methoxy-1,2,3,4-tetrahydroisoquinoline(EEE-6)

To a solution of EEE-5 (195.0 mg, 0.679 mmol) in DCM (7.00 mL) was addedTFA (0.70 mL), followed by aqueous HCHO (37%, 110 mg, 1.36 mmol). Afterthe addition, the reaction mixture was stirred at 25° C. for 3 hours.The reaction mixture was diluted in H₂O and neutralized by sat. Na₂CO₃.The mixture was partitioned with EtOAc and H₂O. The organic layer wasdried over Na₂SO₄ and concentrated to afford the crude product which waspurified by prep-TLC (EtOAc:petroleum ether=1:1) to afford theintermediate (170 mg) which was suspended in aq. HCl (24%, 2 mL) andheated at 110° C. for 3 hours. The reaction mixture was neutralized withsat. Na₂CO₃ then partitioned between EtOAc and H₂O. The organic layerwere evaporated to afford the crude product which was purified byprep-TLC thin layer chromatography (EtOAc:petroleum ether=1:0) to affordthe product EEE-6 (50.0 mg, 37%) as a yellow gum. 1H NMR (400 MHz,DMSO-d₆) δ ppm 7.22 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.76 (s,3H), 3.70 (s, 2H), 2.91 (t, J=6.0 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H)

Step 6—Synthesis of 5-chloro-1,2,3,4-tetrahydroisoquinolin-8-ol (EEE-7)

To a solution of EEE-6 (50.0 mg, 0.253 mmol) in DCM (4.00 mL) was addedBBr₃ (0.40 mL, 4.20 mmol) at 0° C. After the addition, the reactionmixture was stirred at 25° C. for 1 hour. The reaction mixture wasquenched with MeOH and basified by sat. K₂CO₃ to pH 11-12. The mixturewas extracted with EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated to afford the crude product which was purified by prep-TLC(MeOH:DCM=1:10) to afford EEE-7 (50 mg, >99%) as a yellow gum and useddirectly in the next step. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.05 (d, J=8.5Hz, 1H), 6.51 (d, J=9.3 Hz, 1H), 4.00 (s, 2H), 3.16 (t, J=6.0 Hz, 2H),2.79 (t, J=6.1 Hz, 2H)

Step 7—Synthesis of tert-butyl5-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-19)

To a solution of EEE-7 (50 mg, 0.272 mmol) in DCM (5.00 mL) and MeOH(1.00 mL) was added Boc₂O (65 mg, 0.300 mmol) followed by Et₃N (68.9 mg,0.681 mmol). After the addition, the reaction mixture was stirred at 25°C. for 2.5 hours. The reaction mixture was neutralized by aq. HCl (0.1M) to pH 4-5 at 0° C. The resulting mixture was partitioned between DCMand H₂O. The organic layer was separated, washed with brine, dried overNa₂SO₄ and concentrated to afford the crude product which was purifiedby prep-TLC (MeOH:DCM=1:10) to afford TP-19 (50 mg, 65%) as a whitesolid.

Examples 154 & 155 were made in a similar fashion to Example 78 inScheme CC using the appropriate NBoc-protected tetrahydroisoquinoline instep 1.

431 [M + 1] (1S,2S,3S,5R)-3-((6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O)δ ppm 8.85 (s, 1H), 7.81 (d, J = 3.8 Hz, 1H), 7.14-7.05 (m, 3H), 6.89-6.59 (m, 1H), 5.35 (q, J = 9.0 Hz, 1H), 4.86-4.82 (m, 1H), 4.70-4.67 (m,1H), 4.37 (s, 2H), 4.32 (d, J = 4.8 Hz, 1H), 3.49 (t, J = 6.1 Hz, 2H),3.15- 3.02 (m, 3H), 2.90 (s, 3H), 2.26-2.15 (m, 1H)

413 [M + 1] (1S,2S,3S,5R)-3-((5-fluoro-6-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.62 (s, 1H), 7.54 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 5.8Hz, 1H), 6.74 (d, J = 3.8 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 4.73 (dd, J= 5.0, 8.8 Hz, 1H), 4.66 (br s, 1H), 4.24 (s, 2H), 4.17 (d, J = 4.5 Hz,1H), 3.39 (t, J = 6.3 Hz, 2H), 3.00-2.93 (m, 3H), 2.72 (s, 3H), 2.26 (d,J = 1.8 Hz, 3H), 2.21 (ddd, J = 4.1, 9.3, 13.9 Hz, 1H)

Example 156 (SchemeFFF)—(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)cyclopentane-1,2-diol(FFF-4)

Step 1: Synthesis of(1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-ol(FFF-1)

To a solution of BB-2 (650 mg, 2.06 mmol) in dioxane (0.3 mL) and H₂O(0.3 mL) was added lithium hydroxide (494 mg, 20.6 mmol). The reactionwas heated at 90° C. overnight. The reaction mixture was cooled to r.t.,diluted with H₂O, extracted with 20% isopropyl alcohol/DCM, the organiclayers were combined and purified by ISCO 4 g with 100% EtOAc to 10%MeOH/EtOAc to give 424 mg of FFF-1 (96% yield) as a colorless oil whichsolidified on standing.

LCMS [M+1] 216.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.22 (dt,J=15.16, 2.14 Hz, 1H) 2.73 (s, 3H) 3.00 (ddd, J=15.25, 9.20, 7.70 Hz,1H) 4.89 (br. s., 1H) 5.37 (dq, J=9.23, 2.22 Hz, 1H) 5.58 (br. s., 1H)5.85 (dd, J=5.50, 2.45 Hz, 1H) 6.25-6.33 (m, 1H) 6.54 (d, J=3.55 Hz, 1H)7.23 (d, J=3.55 Hz, 1H) 8.69 (s, 1H)

Step 2: Synthesis of tert-butyl4-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate(FFF-2)

To a solution of FFF-1 (100 mg, 0.465 mmol) in THF (3 mL, c=0.2 M) wasadded sodium hydride (27.9 mg, 0.697 mmol) in small batches. Afterstirring at r.t. for 10 min, tert-butyl4-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (TP-20)(125 mg, 0.465 mmol) was added. The resulting reaction mixture wasstirred at r.t. for 3.5 hrs, and then quenched with H₂O, partitionedbetween EtOAc (20 mL) and H₂O (20 mL). The organic phase was separated,washed with brine, dried over Na₂SO₄, concentrated, purified by columnchromatography with 5-10% MeOH/EtOAc to afford 150 mg of FFF-2 (72%yield) as a light yellow foam solid.

LCMS [M+1] 449.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H)1.87 (d, J=15.04 Hz, 1H) 2.66 (s, 3H) 2.80 (t, J=4.77 Hz, 2H) 3.15 (dt,J=15.31, 7.81 Hz, 1H) 3.57-3.65 (m, 1H) 3.65-3.75 (m, 1H) 4.33 (d,J=17.61 Hz, 1H) 4.44 (d, J=17.12 Hz, 1H) 5.98 (dt, J=4.31, 1.94 Hz, 1H)6.01-6.07 (m, 1H) 6.07-6.14 (m, 1H) 6.33 (br. s., 1H) 6.52 (d, J=3.18Hz, 1H) 7.20 (d, J=3.67 Hz, 1H) 8.51 (s, 1H) 8.70 (s, 1H)

Step 3: Synthesis of tert-butyl4-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate(FFF-3)

Compound FFF-2 was treated in similar procedure as step 3 in Scheme BBto give FFF-3 (50 mg, 33%).

LCMS [M+1] 483.20. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H)2.36-2.50 (m, 1H) 2.76 (s, 3H) 2.91 (t, J=5.81 Hz, 2H) 3.06-3.22 (m, 1H)3.62-3.84 (m, 2H) 4.13 (s, 1H) 4.36-4.50 (m, 2H) 4.53 (d, J=6.24 Hz, 1H)4.93-5.05 (m, 1H) 5.45 (td, J=7.12, 3.12 Hz, 1H) 5.64 (br. s., 1H) 6.61(d, J=3.67 Hz, 1H) 7.23 (d, J=3.67 Hz, 1H) 8.64 (s, 1H) 8.76 (s, 1H)

Step 4: Synthesis of(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)cyclopentane-1,2-diol(FFF-4)

Compound FFF-3 was treated to standard deprotection condition similar tostep 3 in Scheme CC to yield FFF-4 (24 mg, 100%).

LCMS [M+1] 383.10. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.11 (m, 1H)2.92 (s, 3H) 2.94-3.02 (m, 1H) 3.06 (br. s., 2H) 3.48 (br. s., 2H) 4.11(d, J=3.42 Hz, 1H) 4.25 (br. s., 2H) 4.66 (dd, J=8.86, 4.58 Hz, 1H) 5.22(q, J=8.93 Hz, 1H) 5.28-5.37 (m, 1H) 7.20 (br. s., 1H) 8.09 (br. s., 1H)8.69 (s, 1H) 9.18 (br. s., 1H) 9.71 (br. s., 1H) 9.87 (br. s., 1H)

Example 157 (SchemeGGG)—(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)cyclopentane-1,2-diol(GGG-5) Scheme GGG

Step 1: Synthesis of tert-butyl8-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (GGG-2)

To a solution of tert-butyl8-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (GGG-1) (250mg, 0.999 mmol) in CH₃CN (2.5 mL) was added POCl₃ (2.5 mL) slowly, andheated at 90° C. overnight. The reaction mixture was neutralized by std.NaHCO₃, the solvent was removed by rotavapor. The residue was added MeOH10 mL, the slurry was added (BOC)₂ (337 mg, 1.50 mmol, 0.355 mL) andDIPEA (258 mg, 2.00 mmol, 0.331 mL), stirred at r.t. for 30 min. Theorganic solvent was rotavapored, EtOAc and H₂O were added, extractedwith EtOAc, the organic layer was concentrated, purified by columnchromatography with 30% EtOAc/heptane to give 240 mg of GGG-2 (89%yield) as a colorless oil.

LCMS [M+1] 269.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.84 (t, J=5.69 Hz, 2H) 3.66 (t, J=5.81 Hz, 2H) 4.56 (s, 2H) 7.03 (d,J=5.01 Hz, 1H) 8.17 (d, J=5.01 Hz, 1H)

Step 2: Synthesis of tert-butyl8-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate(GGG-3)

To a solution of FFF-1 (92 mg, 0.43 mmol) and GGG-2 (115 mg, 0.427 mmol)in DMSO (4.27 mL, c=0.1 M) was treated with potassium butoxide (61.8 mg,0.534 mmol, 0.534 mL, 1.0 M). The reaction was heated to 120° C. for 15min. The reaction was cooled to r.t., diluted with H₂O and EtOAc (10 mLeach). The aqueous phase was extracted with EtOAc (10 mL). The combinedorganics were washed with H₂O (2×15 mL), brine (15 mL), and dried overNa₂SO₄. The sample was concentrated and purified by preparative HPLC togive 40 mg of GGG-3 as a brown solid (21% yield).

LCMS [M+1] 448.20. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.56 (m,9H) 1.94 (d, J=14.92 Hz, 1H) 2.63 (s, 3H) 2.68-2.81 (m, 2H) 3.20 (dt,J=15.13, 7.78 Hz, 1H) 3.55-3.69 (m, 2H) 4.33-4.45 (m, 1H) 4.49 (br. s.,1H) 6.06 (br. s., 2H) 6.11 (d, J=4.03 Hz, 1H) 6.45 (br. s., 1H) 6.62(br. s., 1H) 6.68 (d, J=5.01 Hz, 1H) 7.39 (br. s., 1H) 7.92 (d, J=5.14Hz, 1H) 8.84 (br. s., 1H)

Step 3: Synthesis of tert-butyl8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate(GGG-4)

Compound GGG-3 was treated in similar procedure as step 3 in Scheme BBto give GGG-4 (7.3 mg, 17%).

LCMS [M+1] 481.90. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 10H)2.43-2.54 (m, 1H) 2.75 (s, 3H) 2.81 (t, J=5.75 Hz, 2H) 3.03 (br. s., 1H)3.63-3.71 (m, 2H) 4.38 (br. s., 1H) 4.47 (br. s., 3H) 4.66 (br. s., 1H)5.03-5.12 (m, 1H) 5.25-5.32 (m, 1H) 5.48 (s, 1H) 6.60 (d, J=3.55 Hz, 1H)6.77 (d, J=5.26 Hz, 1H) 7.29 (d, J=3.79 Hz, 1H) 7.93 (d, J=5.14 Hz, 1H)8.77 (s, 1H)

Step 4: Synthesis of(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)cyclopentane-1,2-diol(GGG-5)

Compound GGG-4 was treated to standard deprotection condition similar tostep 3 in Scheme CC to yield GGG-5 (6 mg, 90%).

LCMS [M+1] 382.20 ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.02 (m, 1H)2.86-2.92 (m, 3H) 2.92-2.98 (m, 1H) 3.01 (t, J=5.99 Hz, 2H) 3.57 (s, 2H)4.08 (d, J=4.03 Hz, 1H) 4.20 (br. s., 2H) 4.66 (dd, J=8.93, 4.52 Hz, 1H)5.15-5.23 (m, 1H) 5.23-5.29 (m, 1H) 6.91 (d, J=5.26 Hz, 1H) 7.16 (d,J=3.30 Hz, 1H) 7.99-8.06 (m, 2H) 9.13 (s, 1H) 9.52 (br. s., 1H) 9.64(br. s., 1H)

Example 158 (SchemeHHH)—(1S,2R,3R,5S)-3-((2-methylpyrimidin-4-yl)oxy)-5-((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(HHH-6)

Step 1: Synthesis of tert-butyl8-(((1S,4R)-4-((tert-butoxycarbonyl)oxy)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(HHH-1)

Vial A:

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was addedTris(benzylideneacetone)dipalladium(0)chloroform adduct (44.7 mg, 0.043mmol) and MFCD02684551 (R,R)-DACH-Naphthyl Trost Ligand (102 mg, 0.129mmol). The vial was vacuum purged with argon under dynamic vacuum andDCE (3.6 mL), which had been sparged with argon for 30 minutes, wasadded. The solution was stirred for 30 minutes at rt at which point abright orange solution of ligated catalyst was obtained. At this stageVial B was prepared.

Vial B:

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was added tert-butyl8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (538 mg, 2.16 mmol),and di-tert-butyl-((1R,3S)-cyclopent-4-ene-1,3-diyl)-bis(carbonate)(BB-1) (prepared as reported in J. Am. Chem. Soc. 2006, 128, 6054-6055)(778 mg, 2.59 mmol). The vial was vacuum purged with argon under dynamicvacuum and DCE (3.6 mL), which had been sparged with argon for 30minutes, was added followed by the addition of the contents of Vial Avia airtight syringe. The reaction was stirred under argon at rt for 14hours. The reaction was concentrated under vacuum and purified via flashcolumn chromatography (24g SiO2, Isco, 100% Hept. to 100% EtOAc, 20 mLfractions) to afford HHH-1 (973 mg, >95%) as a yellow foam. LCMS[M+H-Boc-isobutylene]=276 observed; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.12 (t, J=7.9 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H),6.22 (td, J=1.4, 5.7 Hz, 1H), 6.18-6.09 (m, 1H), 5.47 (t, J=5.8 Hz, 1H),5.15 (t, J=5.7 Hz, 1H), 4.59-4.40 (m, J=8.2 Hz, 2H), 3.74-3.54 (m, 2H),3.05 (td, J=7.4, 14.5 Hz, 1H), 2.81 (t, J=5.7 Hz, 2H), 1.96 (td, J=4.5,14.5 Hz, 1H), 1.52-1.47 (m, 18H).

Step 2: Synthesis of tert-butyl8-(((1S,2S,3R,4R)-4-((tert-butoxycarbonyl)oxy)-2,3-dihydroxycyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(HHH-2)

To a scintillation vial, equipped with a magnetic stirbar and containingHHH-1 (225 mg, 0.521 mmol), was added DCM (2.6 mL). To the solution wasadded 4-Methylmorpholine-N-oxide (NMO) (0.32 mL, 1.50 mmol) as a 50 wt %solution in water followed by the dropwise addition of osmium tetraoxide(130 μL, 0.02 mmol) as a 4 wt % solution in water. The reaction wasstirred at rt for 23 hours. The reaction was transferred to a separatoryfunnel with DCM, diluted with water and further diluted with 1M NaHSO3.The phases were separated and the aqueous phase was extracted with 3portions of DCM. The combined organic extracts were dried (MgSO4),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (12g SiO2, Isco, 100% Hept. to 100%EtOAc, 9 mL fractions) to afford HHH-2 (211 mg, 87%) as a white solid.LCMS [M+H-Boc-isobutylene]=310 observed; 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.12 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.71 (d, J=8.2 Hz,1H), 4.90 (td, J=5.8, 9.0 Hz, 1H), 4.69-4.59 (m, 1H), 4.45 (s, 2H), 4.34(s, 1H), 4.26 (br. s., 1H), 3.63 (d, J=5.7 Hz, 2H), 2.81 (t, J=5.7 Hz,3H), 2.03-1.91 (m, J=5.7, 9.3 Hz, 1H), 1.53-1.48 (m, 18H).

Step 3: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-6-((tert-butoxycarbonyl)oxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(HHH-3)

To a reaction vial, equipped with a magnetic stirbar and containingHHH-2 (211 mg, 0.453 mmol), was added acetone (0.29 mL),4-toluenesulfonic acid monohydrate (172 mg, 0.906 mmol) and2,2-dimethoxypropane (0.56 mL, 4.53 mmol). The reaction was stirred atrt for 1 hour. The reaction was transferred to a separatory funnel withEtOAc and water. The biphasic mixture was diluted with sat. NaHCO₃ andthe phases were separated. The organic phase was washed with 1 portionhalf sat. NaHCO₃ and the combined aqueous washed were back extractedwith 1 portion EtOAc. The combined organic phases were dried (MgSO4),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (12g SiO2, Isco, 100% Hept to 100%EtOAc, 9 mL fractions) to afford HHH-3 (140.5 mg, 61%) as a white solid.LCMS [M+H-Boc-isobutylene]=350 observed; 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.12 (s, 1H), 6.73 (t, J=8.1 Hz, 2H), 4.94 (d, J=4.6 Hz, 1H),4.80-4.66 (m, 3H), 4.61-4.43 (m, 2H), 3.63 (s, 2H), 2.80 (t, J=5.6 Hz,2H), 2.47 (td, J=5.4, 15.4 Hz, 1H), 2.25 (td, J=1.5, 15.4 Hz, 1H), 1.49(s, 12H), 1.45 (s, 9H), 1.31 (s, 3H).

Step 4: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(HHH-4)

To a microwave vial, equipped with a magnetic stirbar and containingHHH-3 (134.5 mg, 0.266 mmol) was added dioxane (1.3 mL) and water (1.3mL). To the solution was added lithium hydroxide (63.7 mg, 2.66 mmol)and the vial was sealed with a Teflon cap. The vial was placed in aheating block and stirred at 100° C. for 19 hours. The vial was removedfrom the heating block and allowed to cool to rt. The solution wastransferred to a separatory funnel with EtOAc and diluted with water.The phases were separated and the aqueous phase was extracted with 3portions of EtOAc. The combined organic extracts were dried (MgSO4),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (4g SiO2, Isco, 100% Hept. to 100%EtOAc, 9 mL fractions) to afford HHH-4 (97.3 mg, 90%) as a white foam.LCMS [M+H-Boc]=306 observed; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.17(t, J=7.9 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.75(dd, J=5.4, 7.8 Hz, 2H), 4.67 (dd, J=1.3, 5.6 Hz, 1H), 4.55-4.33 (m,2H), 4.27 (d, J=4.6 Hz, 1H), 3.78-3.49 (m, 2H), 2.82 (t, J=5.7 Hz, 2H),2.42 (td, J=5.0, 15.0 Hz, 1H), 2.10 (d, J=15.0 Hz, 1H), 1.49 (s, 9H),1.46 (s, 3H), 1.31 (s, 3H).

Step 5: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-((2-methylpyrimidin-4-yl)oxy)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(HHH-5)

To an oven dried reaction vial, equipped with a magnetic stirbar andcontaining HHH-4 (43 mg, 0.110 mmol), was added DMF (0.53 mL) and sodiumhydride (8.5 mg, 0.210 mmol) as a 60 wt % dispersion in mineral oil. Thesolution was stirred at rt for 1 hour to produce a dark brown solutionof the sodium alkoxide. To the solution was added4-chloro-2-methylpyrimidine (16.4 mg, 0.127 mmol) and the vial wasplaced in a heating block and heated at 115° C. for 16 hours. Thereaction was quenched carefully by the dropwise addition of water. Thesolution was further diluted with water and transferred to a separatoryfunnel with EtOAc. The phases were separated and the aqueous phase wasextracted with 4 portions of a 3:1 mixture of DCM/IPA. The combinedorganic extracts were washed with 1 portion brine, dried (MgSO4),filtered, and concentrated under vacuum. The crude HHH-5 was used in thenext step without further purification. LCMS [M+H-Boc]=398 observed

Step 6: Synthesis of(1S,2R,3R,5S)-3-((2-methylpyrimidin-4-yl)oxy)-5-((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(HHH-6)

To a round bottom flask, equipped with a magnetic stirbar and containingHHH-5 (53 mg, 0.11 mmol, crude from step 5) was added water (1.0 mL) andTFA (0.5 mL). The solution was stirred at rt for 1 hour. The reactionwas transferred to a separatory funnel with DCM and adjusted to basic pHwith sat. NaHCO₃aq. The phases were separated and the aqueous phase wasextracted with 4 portions of a 3:1 mixture of DCM/IPA. The combinedorganic extracts were washed with 1 portions sat. NaHCO₃aq., dried(MgSO4), filtered, and concentrated under vacuum. The crude residue waspurified by prep-HPLC (Lux Cellulose-1 4.6×100 mm 3p column, 20%MeOH/DEA @ 120 bar, 4 mL/min) to afford HHH-6 (7.06 mg, 19% over 2steps) as a white solid. LCMS [M+H]=358 observed; [α]²² _(D)=+3.7°(c=0.1, MeOH); 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.05 (d, J=6.4 Hz,1H), 7.15 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.79 (d, J=7.6 Hz,1H), 6.67 (d, J=6.5 Hz, 1H), 4.68 (br. s, 2H), 4.61 (td, J=4.2, 8.1 Hz,1H), 4.26 (t, J=4.3 Hz, 1H), 4.12 (td, J=4.9, 7.4 Hz, 1H), 4.02-3.90 (m,3H), 2.90 (t, J=5.7 Hz, 2H), 2.74 (td, J=7.7, 15.0 Hz, 1H), 2.47 (s,3H), 1.62 (td, J=4.7, 14.6 Hz, 1H).

Synthesis of 2-(benzyloxy)-5-fluoro-4-methylbenzoic acid (III-4)

Step 1—Synthesis of methyl 2-(benzyloxy)-4-bromo-5-fluorobenzoate(III-2)

To a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate III-1 (1.62g, 6.505 mmol) in DMF (20 mL) was added K₂CO₃ (2.7 g, 19.5 mmol) andBnBr (2.23 g, 13 mmol). The mixture was stirred at 16° C. for 3 hrs. Themixture was diluted with water (100 mL). Then the mixture was extractedwith EtOAc (50 mL×2). The organic layers were collected, dried andevaporated to give the crude product which was purified by flashchromatography, eluted with petroleum ether/EtOAc from 0-10% to give theIII-2 (1.8 g, 82%) as a white solid and used directly in the next step.

Step 2—Synthesis of methyl 2-(benzyloxy)-5-fluoro-4-methylbenzoate(III-3)

A mixture of III-2 (2 g, 5.87 mmol), Pd(Ph₃P)₄ (339 mg, 0.293 mmol) inTHF (2 0 mL) was degassed with N₂ four times, then added AlMe₃ (7.87 mL,15.7 mmol, 2M) at 0° then reaction stirred at 80° C. for 24 hours. Thereaction was then quenched with aq. potassium sodium tartratetetrahydrate, extracted with EtOAc three times, the combined organiclayers were dried over Na₂SO₄, removed the solvent in vacuum, theresidue was purified by flash biotage (petroleum ether/EtOAc=0-5%) togive III-3 (660 mg, 41%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm7.57-7.47 (m, 3H), 7.43-7.37 (m, 2H), 7.36-7.30 (m, 1H), 6.84 (d, J=6.0Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 2.29 (d, J=2.0 Hz, 3H)

Step 3—Synthesis of 2-(benzyloxy)-5-fluoro-4-methylbenzoic acid (III-4)

To a solution of III-3 (0.71 g, 2.59 mmol) in MeOH (4 mL) was added asolution of LiOH.H₂O (326 gm, 7.77 mmol) in H₂O (4 mL). The reactionmixture was stirred at 20° C. for 2 hours. The reaction solution wasevaporated to remove most of the methanol, and then residue was adjustedto pH-2 with 1N HCl. White solids formed and extracted with EtOAc (20mL×2). The organic layers were dried and evaporated to give III-4 (670mg, 99.5%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.76 (br.s., 1H), 7.83 (d, J=9.5 Hz, 1H), 7.52-7.37 (m, 5H), 6.96 (d, J=6.0 Hz,1H), 5.26 (s, 2H), 2.35 (s, 3H)

Example 159 (SchemeJJJ)—(1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(JJJ-3)

Step 1—Synthesis of5-chloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)benzonitrile(JJJ-1)

To a dry microwave vial (purged with N₂) was added BB-2 (100 mg, 0.317mmol), 5-chloro-2-hydroxybenzonitrile (56 mg, 0.37 mmol), Cs₂CO₃ (114mg, 0.35 mmol), Pd₂(dba)₃ (8.2 mg, 0.008 mmol) and DPPP (7.85 mg, 0.019mmol). Then the vial was purged with N₂ three times and DCE (1.5 mL,sparged with N₂ for 30 mins) was added. The black mixture was stirred at20° C. for 1 hour. Then the reaction mixture was directly purified byprep-TLC (Petroleum ether:EtOAc=1/4) to give JJJ-1 (83 mg, 75%, as ayellow gum. LCMS [M+1] 351; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H),7.56 (d, J=2.8 Hz, 1H), 7.50 (dd, J=2.6, 8.9 Hz, 1H), 7.41 (d, J=3.8 Hz,1H), 7.00 (d, J=9.0 Hz, 1H), 6.63 (d, J=3.5 Hz, 1H), 6.40 (td, J=1.9,5.5 Hz, 1H), 6.26 (dd, J=2.4, 5.6 Hz, 1H), 6.14-6.08 (m, 1H), 5.44 (d,J=7.0 Hz, 1H), 3.21-3.11 (m, 1H), 2.73 (s, 3H), 2.04 (td, J=3.2, 14.9Hz, 1H)

Step 2—Synthesis of5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile (JJJ-2)

To a mixture of JJJ-1 (83 mg, 0.237 mmol) in DCM (6 mL)/H₂O (0.2 mL) wasadded NMO (96 mg, 0.71 mmol) and OsO₄ (4% in t-BuOH, 80 mg, 0.013 mmol)at 20° C. The brown mixture was stirred at 20° C. for 6 hours. Themixture was diluted with DCM (5 mL) and quenched by sat.Na₂SO₃ (2 mL)and separated. The organic layer was washed with brine (5 mL). Thecombined aqueous were extracted with DCM (5 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to yield crudeproduct (100 mg) as a light yellow solid, which was purified by prep-TLC(EtOAc:MeOH=10:1) to yield JJJ-2 (40 mg, 44%) as a white solid. LCMS[M+1] 385; ¹H NMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H), 7.73 (d, J=2.5 Hz,1H), 7.66 (d, J=3.5 Hz, 1H), 7.63 (dd, J=2.6, 9.2 Hz, 1H), 7.30 (d,J=9.0 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 5.35-5.26 (m, 1H), 4.69 (dd,J=4.9, 8.4 Hz, 1H), 4.21 (d, J=4.5 Hz, 1H), 3.04 (ddd, J=6.8, 9.8, 14.8Hz, 1H), 2.71 (s, 3H), 2.17 (ddd, J=3.0, 7.7, 14.7 Hz, 1H)

Step 3—Synthesis of(1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (JJJ-3)

A mixture of JJJ-2 (40 mg, 0.104 mmol) and Raney-Ni (8 mg) in EtOH (7mL)/NH₃.H₂O (0.5 mL) was degassed with H₂ four times. The mixture wasstirred at 20° C. under H₂ balloon for 20 hrs. The mixture was filteredand the filtrate was concentrated in vacuo to afford a white solid,which was purified by prep-TLC (DCM:MeOH:NH₃.H₂O=10:1:0.1) to yieldproduct (˜20 mg) as yellow gum and lyophilized. The material waspurified again by prep-HPLC to give JJJ-3 (9 mg, 22%). LCMS [M+1] 389;¹H NMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H), 7.56 (d, J=3.8 Hz, 1H), 7.42(d, J=2.5 Hz, 2H), 7.21 (d, J=8.8 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 5.11(q, J=9.1 Hz, 1H), 4.82-4.76 (m, 2H), 4.29 (dd, J=2.1, 5.1 Hz, 1H),4.26-4.15 (m, 2H), 3.06-2.92 (m, 1H), 2.72 (s, 3H), 2.37 (ddd, J=5.0,9.7, 14.4 Hz, 1H)

Examples 160 & 161 were prepared in using similar chemistry in Scheme Ausing (4-chloro-3-fluorophenyl)magnesium bromide for step 8.

Example 160

392 [M + 1] (1S,2R,3R,5R)-3-((S)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.59 (s, 1H), 7.65 (d, J = 3.8 Hz, 1H), 7.53 (t, J = 8.0Hz, 1H), 7.40 (dd, J = 1.8, 10.5 Hz, 1H), 7.27 (dd, J = 1.9, 8.2 Hz,1H), 6.69 (d, J = 3.5 Hz, 1H), 5.73 (d, J = 4.8 Hz, 1H), 5.02-4.93 (m,1H), 4.80 (d, J = 7.0 Hz, 1H), 4.64-4.58 (m, 1H), 4.56 (d, J = 3.8 Hz,1H), 4.28 (td, J = 6.1, 9.9 Hz, 1H), 3.95-3.90 (m, 1H), 2.63 (s, 3H),2.29-2.21 (m, 1H), 2.02 (td, J = 8.6, 12.9 Hz, 1H), 1.67-1.57 (m, 1H)Example 161

392 [M + 1] (1S,2R,3R,5R)-3-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.59 (s, 1H), 7.65 (d, J = 3.5 Hz, 1H), 7.51 (t, J = 8.0Hz, 1H), 7.35 (dd, J = 1.5, 10.5 Hz, 1H), 7.22 (dd, J = 1.9, 8.2 Hz,1H), 6.71-6.67 (m, 1H), 5.71 (d, J = 4.8 Hz, 1H), 4.97-4.88 (m, 1H),4.86 (d, J = 6.5 Hz, 1H), 4.82 (t, J = 4.9 Hz, 1H), 4.67 (d, J = 4.5 Hz,1H), 4.26-4.18 (m, 1H), 3.90 (q, J = 4.9 Hz, 1H), 2.63 (s, 3H),2.27-2.18 (m, 1H), 1.89-1.71 (m, 2H)

Example 162 was made in a similar fashion to Example 99 in Scheme NNusing isoquinolin-8-ol in step 2.

Example 162 isoquinolin-8-ol

396 LCMS [M + 1] (1S,2S,3R,5S)-3-(4-amino-5- fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (isoquinolin-8- yloxy)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD-d₄) δ ppm 9.62 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 8.04(s, 1H), 7.79 (d, J = 5.5 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.52 (d, J= 8.3 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 5.19(q, J = 9.0 Hz, 1H), 4.68 (br dd, J = 4.9, 8.9 Hz, 2H), 4.33 (br d, J =4.8 Hz, 1H), 3.12-3.01 (m, 1H), 2.29- 2.18 (m, 1H)

Synthesis of 6-hydroxy-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(TP-21) and tert-butyl6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-22)(Scheme KKK)

Step 1—Synthesis of methyl2-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-hydroxybenzoate (KKK-2)

A solution of methyl 2,6-dihydroxybenzoate (1.2 g, 7.14 mmol),tert-butyl (2-bromoethyl)carbamate (2.33 g, 7.14 mmol) and K₂CO₃ (2.5 g,17.8 mmol) in DMF (10 mL) was stirred at 15° C. for 32 h. Water wasadded to the reaction mixture and extracted with EtOAc three times. Thecombined organic layers were dried over sodium sulfate, concentrated invacuo, and the residue was purified by flash chromatography (petroleumether/EtOAc=10-20%) to give compound KKK-2 (900 mg, 41%) as a whitesolid and used in the next step directly.

Step 2—Synthesis of methyl2-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-hydroxybenzoate (KKK-3)

To a solution of compound KKK-2 (900 mg, 2.89 mmol) in DCM (10 ml) wasadded TFA (2 mL) at 0-5° C., then the reaction mixture was stirred at15° C. for 2 h. The solvent was removed and the residue (700 mg, >99%)was used to next step directly.

Step 3—Synthesis of 6-hydroxy-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(TP-21)

To a solution of compound KKK-3 (700 mg, 3.31 mmol) in i-PrOH (6 mL) wasadded TEA (3.35 g, 33.1 mmol) at 15° C., then the reaction mixture wasstirred at 95° C. for 6 h. The solvent was removed, and the residue waspurified by flash chromatography (20 g, petroleum ether/EtOAc=10-50%) togive compound TP-21 (480 mg, 81%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 12.61 (s, 1H), 7.33-7.29 (m, 1H), 6.70 (d, J=8.3 Hz, 1H),6.57 (br. s., 1H), 6.53 (d, J=8.0 Hz, 1H), 4.41-4.35 (m, 2H), 3.57 (q,J=4.8 Hz, 2H)

Step 4—Synthesis of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-ol (KKK-4)

To a solution of compound TP-21 (100 mg, 0.56 mmol) in anhydrous THF (2mL) was added BH₃-Me₂S (127 mg, 1.67 mmol) at 0° C. drop-wise under N₂.After the addition, the mixture was heated to 70° C. (reflux) for 3hours. The reaction mixture was then quenched with 1 mL of MeOHcarefully at −10-20° C., then added another 6N HCl 10 mL, then refluxedfor 3 h, removed the most solvent under vacuum, then the residue wasadjusted pH 8-9 with K₂CO₃, extracted with EtOAc three times. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the crude compound KKK-4 (0.5 g, >99%). LCMS [M+1]166

Step 5—Synthesis of tert-butyl6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-22)

Crude compound KKK-4 (500 mg, 0.61 mmol) was dissolved in DCM (5 mL) andMeOH (5 mL). (Boc)₂O (132 mg, 0.605 mmol) and Et₃N (184 mg, 1.82 mmol)were added and the reaction mixture was stirred at 15° C. for 16 hours.DCM (10 mL) was added, then washed with acetic acid (5 mL) and saturatedNaCl (5 mL). The organic layer was separated, dried and evaporated togive the residue. Then 10 mL MeOH was added to dissolve the residue,then K₂CO₃ (200 mg) was added to the mixture. The reaction mixture wasstirred at 15° C. for 2 hours. DCM (25 mL×2) was added to the solution,the solution was washed acetic acid (5 mL, pH <7) and saturated NaCl (5mL). The organic layers were combined, dried and evaporate to give thecrude product which was purified by prep-TLC to give compound TP-22 (13mg, 8%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.62 (br s,1H), 7.07 (t, J=8.2 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.64 (d, J=7.8 Hz,1H), 4.37 (s, 2H), 4.01-3.92 (m, 2H), 3.79-3.70 (m, 2H), 1.40 (s, 9H)LCMS [M-Boc+1] 210.

Synthesis of tert-butyl6-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-23) (Scheme LLL)

Under an N₂ atmosphere, TP-12 (50 mg, 0.15 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(67 mg, 0.23 mmol), K₃PO₄ (97 mg, 0.46 mmol) and XPhos-Palladacycle (13mg, 0.015 mmol) was added to a vial. DMF (1.60 mL) was added and thereaction solution was heated to 50° C. in a microwave for 16 hours.EtOAc and H₂O were added to dilute the reaction solution. The aqueouswas extracted with EtOAc (3 mL×2). The organic layers were separated,dried and evaporated to give the crude product, which was purified byprep-TLC (petroleum ether/EtOAc=1/1) to give the desired compound TP-23(33 mg, 90%) as a colorless oil. LCMS [M-Boc+1] 316.

Synthesis of tert-butyl6-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-24) (Scheme MMM)

TP-24 was synthesized in a similar fashion to TP-23 (Scheme LLL)starting from TP-11. LCMS [M-Boc+1] 334.

Synthesis of tert-butyl8-hydroxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-25) (Scheme NNN)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(NNN-1)

A mixture of GG-7 (3.00 g, 7.17 mmol), bis(pinacolato)diboron (2.73 g,10.8 mmol), KOAc (1.4 g, 14.3 mmol) and PdCl₂(dppf).CH₂Cl₂ (262 mg, 0.36mmol) in dioxane (30.0 mL) was heated to 80° C. for 16 hours. Water (30mL) was added to dilute the reaction solution then extracted with EtOAc(30 mL×2). The organic layers were combined, dried and evaporated togive the crude product, which was purified by flash chromatography (120g silica gel), eluted with petroleum ether/EtOAc 0-20%, to give NNN-1 (3g, 90%) as a white solid. LCMS [M-Boc+1] 366; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.50-7.45 (m, 2H), 7.43-7.39 (m, 2H), 7.37-7.30 (m, 1H), 7.13 (d,J=2.5 Hz, 2H), 5.15 (br. s., 2H), 4.54-4.38 (m, 2H), 3.59-3.50 (m, 2H),2.77 (t, J=5.5 Hz, 2H), 1.42 (s, 9H), 1.29 (s, 12H)

Step 2—Synthesis of tert-butyl8-(benzyloxy)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(NNN-2)

A vial under argon containing NNN-1 (800 mg, 1.72 mmol),5-iodo-1-methyl-1H-1,2,3-triazole (467 mg, 2.23 mmol), PdCl₂(dppf)-DCM(126 mg, 0.172 mmol), K₂CO₃ (475 mg, 3.44 mmol), DME (10.0 mL) and water(1.00 mL) was capped and heated at 80° C. for 16 hours. Water (10.0 mL)was added to the reaction and extracted with EtOAc (10 mL×2). Theorganic layers were separated, dried and evaporated to give the crudeproduct, which was purified by flash chromatography (80 g), eluted withpetroleum ether/EtOAc (1:1) to give NNN-2 (640 mg, 89%) as a colorlessoil. LCMS [M+1] 421.

Step 3—Synthesis of tert-butyl8-hydroxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-25)

Compound NNN-2 (640 mg, 1.52 mmol) was dissolved in EtOAc (3 mL). Pd/C(162 mg, 1.52 mmol) was added to the above mixture, the reaction mixturewas stirred at 25° C. for 48 hours. The solution was diluted with EtOAc(10 mL) and filtered. The filtrate was evaporated to give the crudeproduct, which was purified by flash chromatography, eluted withpetroleum ether/EtOAc from 0-30%, to give the desired product TP-25 (320mg, 64%) as a white solid. LCMS [M+1] 331; ¹H NMR (400 MHz, DMSO-d₆) δppm 10.04 (s, 1H), 7.82 (s, 1H), 6.91-6.77 (m, 2H), 4.40 (s, 2H), 4.04(s, 3H), 3.56 (m, 2H), 2.78 (m, 2H), 1.45 (s, 9H)

Synthesis of tert-butyl8-hydroxy-6-(thiazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-26) (Scheme OOO)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-6-(thiazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(OOO-1)

A vial under argon containing compound NNN-1 (800 mg, 1.72 mmol),4-bromothiazole (367 mg, 2.23 mmol), Pd(PPh₃)₄(278 mg, 0.241 mmol),K₂CO₃ (523 mg, 3.78 mmol), dioxane (10 mL) and water (1 mL) was cappedand heated at 80° C. for 16 hours. Water (10 mL) was added to thereaction and extracted with EtOAc (10 mL×2). The organic layers wereseparated, dried and evaporated to give the crude product, which waspurified by flash chromatography, eluted with petroleum ether/EtOAc from0-20%) to give OOO-1 (370 mg, 51%) as a colorless oil.

LCMS [M+23] 445

Step 2—Synthesis of 6-(thiazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol(OOO-2)

Compound OOO-1 (320 mg, 0.76 mmol) was dissolved in DCM (10 mL) andcooled to 0° C. in an ice bath. BBr₃ (1.14 g, 4.54 mmol) was added tothe reaction solution and stirred at 25° C. for 16 hours. The reactionsolution was cooled to 0° C. Methanol (3.00 mL) was added to thereaction solution drop-wise followed by water (20 mL). The reactionsolution was washed with DCM (10 mL×2). The aqueous layer was separated.Na₂CO₃ solid was used to adjust the pH to 9. The final solution ofcompound OOO-2 was used for the next step directly. LCMS [M+1]233.

Step 3—Synthesis of tert-butyl8-hydroxy-6-(thiazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-26)

MeOH (5.00 mL) and dioxane (5.00 mL) were added to the solution ofcompound OOO-2 (180 mg, reaction solution aqueous, 40.0 mL), then(Boc)₂O (335 mg, 1.55 mmol) was added to the reaction and stirred at 25°C. for 16 hours. DCM (20 mL) was added to dilute solution. The pH wasadjusted to pH˜3 by the addition of 1N HCl aq. The solution wasseparated and the aqueous layer was extracted with DCM (10 mL). Theorganic layers were combined and washed with saturated NaCl (20.0 mL).The organic layers were separated, dried and evaporated to give thecrude product, which was purified by flash chromatography, eluted withpetroleum ether/EtOAc 0-50% to give the TP-26 (180 mg, 70%) as a yellowsolid. LCMS [M+1]333; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.78 (s, 1H), 9.16(d, J=2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.33 (d, J=1.3 Hz, 1H), 7.24(s, 1H), 4.38 (s, 2H), 3.56 (m, 2H), 2.77 (m, 2H), 1.44 (s, 9H)

Synthesis of tert-butyl8-hydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-28)(Scheme PPP)

Step 1: Synthesis of 3-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (PPP-1)

A solution of 3-methylisoquinolin-8-ol (TP-27) [prepared fromTetrahedron Letters 49 (2008) 3725-3728] (100 mg, 0.628 mmol) inEtOH/AcOH (6 mL/0.2 mL) was added PtO₂ (80 mg, 0.35 mmol), hydrogenatedunder 45 psi H₂ at rt for 16 h. The reaction mixture was filtered andwashed with EtOH, the solvent was evaporated to give crude PPP-1 (103mg, 100%) which was used to the next step without further purification.LCMS [M+1] 163.9.

Step 2: Synthesis of tert-butyl8-hydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-28)

To a solution of PPP-1 (103 mg, 0.628 mmol) in THF (6 mL, 0.1 M) wasadded Boc₂O (225 mg, 1.03 mmol) and K₂CO₃ (356 mg, 2.57 mmol) at 15° C.,stirred at rt for 15 hrs. The solvent was removed, the residue wasdissolved in MeOH, added 0.1 g K₂CO₃, stirred for 2 hrs. The solid wasfiltered and washed with EtOAc, the filtrate was concentrated andpurified by preparative TLC to give TP-28 (70 mg, 42%) as yellow solid.

LCMS [M+1-tBu] 207.9. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.09-7.01 (m,1H), 6.71 (d, J=7.8 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.81 (br d, J=17.6Hz, 1H), 4.63 (br s, 1H), 4.18 (d, J=17.6 Hz, 1H), 3.08 (br dd, J=5.5,16.1 Hz, 1H), 2.55 (br ddd, J=1.8, 14.6, 16.3 Hz, 1H), 1.54-1.43 (s,9H), 1.09 (d, J=6.8 Hz, 3H)

Synthesis of tert-butyl8-hydroxy-6-(oxazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-29) (Scheme QQQ)

Step 1: Synthesis of tert-butyl8-(benzyloxy)-6-(oxazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(QQQ-1)

To the solution of II-1 (265 mg, 0.721 mmol) and p-toluenesulfonylmethylisocyanide (465 mg, 2.38 mmol) in methanol (14.4 mL, c=0.05 M) was addedK₂CO₃ (199 mg, 1.44 mmol), the resulting suspension was refluxedovernight. The reaction mixture was concentrated, EtOAc and H₂O wereadded. The layers were separated; the aqueous was extracted with EtOAc.The organic layers were concentrated, purified by column chromatographywith 35% EtOAc/heptane to give QQQ-1 (100 mg, 34%) as colorless oil.

LCMS [M+1-Boc] 307.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.86 (t, J=5.01 Hz, 2H) 3.67 (t, J=5.62 Hz, 2H) 4.62 (s, 2H) 5.16 (br.s., 2H) 7.06 (s, 1H) 7.08 (s, 1H) 7.31 (s, 1H) 7.35 (d, J=7.21 Hz, 1H)7.41 (t, J=7.34 Hz, 2H) 7.44-7.50 (m, 2H) 7.90 (s, 1H)

Step 2: Synthesis of tert-butyl8-hydroxy-6-(oxazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-29)

Compound TP-29 was prepared from QQQ-1 in a similar method as step 9 inScheme GG (79 mg, 100%).

LCMS [M+1-Boc] 217.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (s, 9H)2.83 (br. s., 2H) 3.67 (t, J=5.69 Hz, 2H) 4.60 (br. s., 2H) 6.95 (br.s., 2H) 7.27 (s, 1H) 7.90 (s, 1H)

Synthesis of tert-butyl8-hydroxy-6-(1H-pyrazol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-30) (Scheme RRR)

Step 1: Synthesis of tert-butyl6-acetyl-8-(benzyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (RRR-1)

Compound RRR-1 was prepared from GG-7 in a similar method as step 1 inScheme JJ (360.0 mg, 80.2%).

Step 2: Synthesis of tert-butyl(E)-8-(benzyloxy)-6-(3-(dimethylamino)acryloyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(RRR-2)

RRR-1 (65 mg, 0.17 mmol) and N,N-dimethylformamide dimethylcetal (0.5mL) were heated at 100° C. overnight. The r×n mixture was concentrated,purified by column chromatography with 70% EtOAc/heptane to give RRR-270 mg (94% yield) as a yellow oil.

LCMS [M+1] 437.20. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9H)2.77-2.92 (m, 2H) 2.92-3.22 (m, 6H) 3.66 (t, J=5.01 Hz, 2H) 4.62 (s, 2H)5.17 (br. s., 2H) 5.66 (d, J=12.35 Hz, 1H) 7.28 (br. s., 1H) 7.32 (d,J=7.21 Hz, 1H) 7.38 (t, J=7.27 Hz, 3H) 7.43-7.49 (m, 2H) 7.80 (d,J=12.35 Hz, 1H)

Step 3: Synthesis of tert-butyl8-(benzyloxy)-6-(1H-pyrazol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(RRR-3)

RRR-2 (70 mg, 0.16 mmol) and hydrazine monohydrate (183 mg, 1.28 mmol,0.178 mL) in 2 mL EtOH was stirred at rt overnight. The reaction mixturewas added EtOAc and H₂O, the layers were separated, the aqueous wasextracted with EtOAc. The organic was combined and washed with brine,dried over Na₂SO₄, concentrated to give RRR-3 58.8 mg (90% yield) as asolid.

LCMS [M+1-tBu] 350.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.76-2.93 (m, 2H) 3.67 (t, J=5.50 Hz, 2H) 4.62 (s, 2H) 5.16 (br. s., 2H)6.59 (d, J=2.32 Hz, 1H) 7.15 (s, 1H) 7.23 (s, 1H) 7.30-7.36 (m, 1H) 7.39(t, J=7.27 Hz, 2H) 7.44-7.49 (m, 2H) 7.62 (d, J=2.20 Hz, 1H)

Step 4: Synthesis of tert-butyl8-hydroxy-6-(1H-pyrazol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-30)

Compound TP-30 was prepared from RRR-3 in a similar method as step 9 inScheme GG (32 mg, 70%).

LCMS [M+1-Boc] 216.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.77 (t, J=5.26 Hz, 2H) 3.62 (t, J=5.50 Hz, 2H) 4.58 (br. s., 2H) 6.46(br. s., 1H) 6.97 (s, 1H) 7.12 (br. s., 1H) 7.50-7.63 (m, 1H)

Examples 163-171 were made in a similar fashion to Example 78 in SchemeCC using the appropriate NBoc-protected tetrahydroisoquinoline in step1.

411 LCMS [M + 1] 6-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)oxy)-3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one ¹H NMR (400 MHz, DMSO-d₆) δppm 8.62 (s, 1H), 8.33 (t, J = 6.1 Hz, 1H), 7.97 (d, J = 3.8 Hz, 1H),7.38 (t, J = 8.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 2.0,5.8 Hz, 2H), 5.35 (d, J = 3.5 Hz, 1H), 5.31-5.23 (m, 1H), 5.08 (d, J =6.8 Hz, 1H), 4.71 (br d, J = 6.3 Hz, 1H), 4.63- 4.56 (m, 1H), 4.11 (brd, J = 4.8 Hz, 2H), 4.00 (br s, 1H), 3.25-3.16 (m, 2H), 2.90-2.80 (m,1H), 2.64 (s, 3H), 1.72 (m, 1H)

397 LCMS [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)cyclopentane-1,2-diol HCl salt¹H NMR (400 MHz, MeOD-d₄) δ ppm = 9.12-8.97 (m, 1H), 8.15- 7.95 (m, 1H),7.36-7.26 (m, 1H), 7.25-7.12 (m, 1H), 7.00-6.88 (m, 1H), 6.75 (d, J =6.5 Hz, 1H), 5.46- 5.33 (m, 1H), 4.81-4.73 (m, 2H), 4.68-4.52 (m, 2H),4.36-4.14 (m, 3H), 3.67-3.56 (m, 2H), 3.12-3.04 (m, 1H), 3.00 (br. s.,3H), 2.40- 2.25 (m, 1H)

447 LCMS [M + 1] (1S,2S,3S,5R)-3-((6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2- diol HCl Salt ¹H NMR (400 MHz, D₂O) δppm 8.85-8.80 (m, 1H), 8.00-7.95 (m, 2H), 7.81 (br dd, J = 1.4, 3.9 Hz,1H), 7.14-7.07 (m, 2H), 7.05 (br d, J = 3.3 Hz, 1H), 5.39-5.27 (m, 2H),4.92-4.82 (m, 1H), 4.30 (br s, 3H), 3.50-3.39 (m, 2H), 3.11-2.99 (m,3H), 2.88 (br s, 3H), 2.20 (br s, 1H)

465 LCMS [M + 1] (1S,2S,3S,5R)-3-((5-fluoro-6-(1H-pyrazol-4-yl)-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol HCl salt¹H NMR (400 MHz, D₂O) δ ppm 8.57 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H),7.51 (d, J = 3.8 Hz, 1H), 7.12 (d, J = 5.8 Hz, 1H), 6.80 (s, 1H), 5.22-5.13 (m, J = 8.9, 8.9, 8.9 Hz, 2H), 4.89-4.84 (m, 1H), 4.66-4.61 (m,1H), 4.39-4.27 (m, 3H), 3.54-3.49 (m, 2H), 3.11-3.04 (m, J = 5.6, 5.6Hz, 2H), 3.04-2.96 (m, 1H), 2.68 (s, 3H), 2.17-2.07 (m, 1H)

462 LCMS [M + 1] (1S,2S,3S,5R)-3-((6-(1-methyl-1H-1,2,3-triazol-5-yl)-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol HCl salt¹H NMR (400 MHz, D₂O) δ ppm 8.93-8.91 (s, 1H), 7.93-7.90 (d, J = 4.0 Hz,1H), 7.88 (s, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.14-7.11 (s, 1H), 7.08 (s,1H), 5.42 (m, 1H), 4.94- 4.86 (m, 2H), 4.46 (s, 2H), 4.40 (m, 1H), 4.10(s, 3H), 3.61-3.54 (m, 2H), 3.24-3.16 (m, 2H), 3.17-3.07 (m, 1H), 2.98(s, 3H), 2.37-2.26 (m, 1H)

464 LCMS [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6- (thiazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol HCl Salt ¹H NMR(400 MHz, D₂O) δ ppm 9.09 (d, J = 1.8 Hz, 1H), 8.90 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H),7.17-7.15 (m, 1H), 5.43 (m, 1H), 4.96 (m, 1H), 4.85-4.83 (m, 1H), 4.43(s, 2H), 4.41 (m, 1H), 3.59- 3.54 (m, 2H), 3.23-3.18 (m, 2H), 3.18-3.11(m, 1H), 2.96 (s, 3H), 2.35-2.26 (m, 1H)

391 LCMS [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((3- methylisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, METHANOL-d4) δ ppm 9.56(s, 1H), 8.57 (s, 1H), 7.71-7.60 (m, 3H), 7.43 (d, J = 8.3 Hz, 1H), 7.13(d, J = 7.3 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1H), 5.30 (q, J = 8.9 Hz, 1H),4.98 (m, 1H), 4.91 (m, 1H), 4.38 (d, J = 5.0 Hz, 1H), 3.16-3.08 (m, 1H),2.72 (s, 3H), 2.70 (s, 3H), 2.45-2.37 (m, 1H)

448 LCMS [M + 1] (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6- (oxazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,METHANOL-d4) δ ppm 8.99 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 3.8 Hz, 1H),7.63 (s, 1H), 7.35 (d, J = 16.6 Hz, 2H), 7.17 (d, J = 3.8 Hz, 1H), 5.40(q, J = 9.3 Hz, 1H), 4.79 (dd, J = 5.0, 9.0 Hz, 1H), 4.43 (s, 2H), 4.26(d, J = 4.5 Hz, 1H), 3.55 (t, J = 6.3 Hz, 2H), 3.23-3.07 (m, 3H), 2.97(s, 3H), 2.33 (ddd, J = 4.1, 9.6, 13.9 Hz, 1H)

447 LCMS [M + 1] (1S,2S,3S,5R)-3-((6-(1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2- diol HCl salt ¹H NMR (400 MHz, D₂O) δppm = 8.88 (s, 1H), 7.86 (d, J = 3.8 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H),7.34 (m, 2H), 7.14 (m, 1H), 6.77 (m, 1H), 5.41 (m, 1H), 4.93 (m, 1H),4.75- 4.70 (m, 1H), 4.44-4.36 (m, 3H), 3.58-3.50 (m, 2H), 3.25-3.07 (m,3H), 2.93 (s, 3H), 2.31 (m, 1H)

Example 172 (Scheme SSS)—Synthesis of(1S,2S,3S,5R)-3-(isoquinolin-8-yloxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(SSS-6)

Step 1: Synthesis of tert-butyl((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)carbonate (SSS-1)

Compound SSS-1 was prepared from BB-2 in a similar method as step 2 inScheme CC to give 274 mg (82% yield) as a colorless oil.

LCMS [M+1] 350.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H)2.18 (ddd, J=14.21, 9.14, 5.26 Hz, 1H) 2.71 (s, 3H) 3.02 (dt, J=14.18,8.07 Hz, 1H) 3.95-4.02 (m, 1H) 4.30 (dd, J=5.38, 2.08 Hz, 1H) 4.51 (dd,J=7.82, 5.50 Hz, 1H) 4.96-5.08 (m, 2H) 6.61 (d, J=3.67 Hz, 1H) 7.29 (d,J=3.67 Hz, 1H) 8.66 (s, 1H)

Step 2: Synthesis of tert-butyl((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbonate (SSS-2)

Compound SSS-2 was prepared from SSS-1 in a similar method as step 3 inScheme P to give 181 mg (59% yield) as a colorless oil.

LCMS [M+1] 390.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 3H)1.50 (s, 9H) 1.58 (s, 3H) 2.38-2.48 (m, 1H) 2.73 (s, 3H) 2.84-2.95 (m,1H) 4.82 (d, J=6.11 Hz, 1H) 4.99 (dd, J=6.54, 3.12 Hz, 1H) 5.06-5.13 (m,1H) 5.21-5.29 (m, 1H) 6.57 (d, J=3.67 Hz, 1H) 7.31 (d, J=3.67 Hz, 1H)8.78 (s, 1H)

Step 3: Synthesis of(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol(SSS-3)

Compound SSS-3 was prepared from SSS-2 in a similar method as step 1 inScheme FFF to give 127 mg (94% yield) as a white solid.

LCMS [M+1] 290.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3H)1.55 (s, 3H) 2.20 (dd, J=15.65, 1.34 Hz, 1H) 2.75 (s, 3H) 2.95-3.08 (m,1H) 4.44-4.50 (m, 1H) 4.80 (d, J=5.38 Hz, 1H) 4.84 (dt, J=10.58, 2.48Hz, 1H) 4.98 (d, J=5.01 Hz, 1H) 6.15 (d, J=9.41 Hz, 1H) 6.55 (d, J=3.67Hz, 1H) 8.73 (s, 1H)

Step 4: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate(SSS-4) and1-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-2,7-naphthyridine(SSS-5)

To a solution of SSS-3 (80.7 mg, 0.279 mmol) in DMF (5.58 mL, c=0.05 M)was added NaH (16.7 mg, 0.419 mmol, 60%). After stirring for 10 min,GGG-2 (75.0 mg, 0.279 mmol) was added. The resulting reaction mixturewas heated at 100° C. for 1.5 h. The reaction was quenched with dilutedNaHCO₃, and then partitioned between ethyl acetate (20 mL) and water (20mL). The organic phase was separated, washed with brine, dried oversodium sulfate, concentrated and purified with column chromatographywith 60% EtOAc/heptane to give SSS-4 (15 mg, 10%)

LCMS [M+1] 522.20. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 3H)1.50 (s, 9H) 1.60 (s, 3H) 2.45 (d, J=14.18 Hz, 1H) 2.72 (s, 3H) 2.76 (t,J=5.38 Hz, 2H) 3.05 (dt, J=14.61, 7.12 Hz, 1H) 3.60 (br. s., 1H) 3.65(br. s., 1H) 4.39 (br. s., 2H) 4.94 (d, J=6.24 Hz, 1H) 5.05 (dd, J=6.17,1.90 Hz, 1H) 5.34 (ddd, J=7.70, 4.95, 2.38 Hz, 1H) 5.60 (br. s., 1H)6.61 (br. s., 1H) 6.69 (d, J=5.14 Hz, 1H) 7.38 (d, J=3.67 Hz, 1H) 7.95(d, J=5.14 Hz, 1H) 8.79 (m, 1H) and eluted with 5% MeOH/EtOAc to giveSSS-5 (35 mg, 30%)

LCMS [M+1] 418.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 3H)1.63 (s, 3H) 2.56 (dt, J=14.98, 3.82 Hz, 1H) 2.72 (s, 3H) 3.04-3.19 (m,1H) 5.11 (d, J=6.11 Hz, 1H) 5.21 (d, J=6.11 Hz, 1H) 5.35-5.46 (m, 1H)5.83 (dt, J=3.97, 2.05 Hz, 1H) 6.61 (d, J=3.67 Hz, 1H) 7.20 (d, J=5.87Hz, 1H) 7.39 (d, J=3.67 Hz, 1H) 7.55 (d, J=5.62 Hz, 1H) 8.22 (d, J=5.87Hz, 1H) 8.70 (br. s., 1H) 8.77 (s, 1H) 9.38 (br. s., 1H)

Step 5: Synthesis of(1S,2S,3S,5R)-3-(isoquinolin-8-yloxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(SSS-6)

Compound SSS-6 was prepared from SSS-5 in a similar method as step 10 inScheme A to give 11.6 mg (36% yield) as a white solid.

LCMS [M+1] 378.10. ¹H NMR (700 MHz, DMSO-d6) δ ppm 2.05-2.15 (m, 1H)2.64-2.72 (m, 3H) 2.98 (ddd, J=14.75, 9.24, 7.48 Hz, 1H) 4.25 (d, J=3.08Hz, 1H) 4.72 (dd, J=8.69, 4.73 Hz, 1H) 5.21 (q, J=8.88 Hz, 1H) 5.48 (dd,J=5.94, 3.30 Hz, 1H) 6.80 (d, J=3.52 Hz, 1H) 7.43 (d, J=5.94 Hz, 1H)7.78-7.89 (m, 2H) 8.24 (d, J=5.72 Hz, 1H) 8.64 (s, 1H) 8.80 (br. s., 1H)9.72 (br. s., 1H)

Example 173 was made in a similar fashion to CC-3 (Example 78) using theappropriate pyrrolopyrimidine in step 1 of Scheme BB and the appropriateN-Boc protected tetrahydroisoquinoline in step 1 of Scheme CC.

424 LCMS [M + 1] 8-(((1S,2S,3S,4R)-4-(5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,3-dihydroxycyclopentyl)oxy)-1,2,3,4-tetrahydroisoquinoline-6- carbonitrile ¹H NMR (400 MHz, MeOD-d4)δ ppm 9.09 (br. s., 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 7.33(s, 1H), 5.38 (q, J = 9.1 Hz, 1H), 4.79 (t, J = 5.1 Hz, 1H), 4.60 (dd, J= 5.3, 9.3 Hz, 1H), 4.44 (s, 2H), 4.19 (d, J = 4.8 Hz, 1H), 3.60-3.50(m, 2H), 3.21- 3.13 (m, 2H), 3.02 (td, J = 8.2, 14.5 Hz, 1H), 2.83-2.79(m, 3H), 2.19 (ddd, J = 4.6, 9.6, 14.1 Hz, 1H)

Example 174 was made in a similar fashion to NN-5 (Example 99) using theappropriate pyrrolopyrimidine in step 1 of Scheme BB and the appropriateN-Boc protected tetrahydroisoquinoline in step 1 of Scheme NN.

441 LCMS [M + 1] 8-(((1S,2S,3S,4R)-4-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,3-dihydroxycyclopentyl)oxy)-1,2,3,4-tetrahydroisoquinoline-6- carbonilrile HCl salt ¹H NMR (400 MHz,MeOD-d4) δ ppm 8.30 (s, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 7.30 (s, 1H),5.29-5.21 (m, 1H), 4.78 (t, J = 5.2 Hz, 1H), 4.62 (dd, J = 5.2, 9.2 Hz,1H), 4.43 (s, 2H), 4.19 (d, J = 5.1 Hz, 1H), 3.57- 3.51 (m, 2H), 3.18(t, J = 6.1 Hz, 2H), 3.09-2.96 (m, 1H), 2.20 (ddd, J = 4.5, 9.7, 14.0Hz, 1H)

Examples 175-179 were made in a similar fashion to SS-5 (Example 121)using the appropriate N-Boc protected tetrahydroisoquinoline in step 1and the appropriate pyrrolopyrimidine in step 2 of Scheme SS. Step 4 inScheme SS was not required for these examples.

433 LCMS [M + H] (1S,2S,3S,5R)-3-((6- chloro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(5-fluoro-2- methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DEUTERIUMOXIDE) δ ppm 9.13 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 4.0Hz, 2H), 5.40 (br d, J = 8.5 Hz, 1H), 4.72 (br d, J = 2.0 Hz, 1H), 4.58(dd, J = 4.8, 9.0 Hz, 1H), 4.32- 4.27 (m, 3H), 3.46 (t, J = 6.1 Hz, 2H),3.09-3.05 (m, 2H), 3.01 (s, 1H), 2.83 (s, 3H), 2.17-2.07 (m, 1H).

433 LCMS [M + H] (1S,2S,3S,5R)-3-((6- chloro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(5-fluoro-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DEUTERIUMOXIDE) δ ppm 8.88 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.01 (d, J = 4.0Hz, 2H), 5.43 (q, J = 9.0 Hz, 1H), 4.89-4.83 (m, 1H), 4.66 (dd, J = 4.8,8.8 Hz, 1H), 4.41-4.30 (m, 3H), 3.52 (t, J = 6.3 Hz, 2H), 3.17-3.05 (m,3H), 3.01 (s, 3H), 2.26-2.07 (m, 1H).

435 LCMS [M + 1] (1S,2S,3S,5R)-3-((5,6- difluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(5-fluoro-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol HCl Salt ¹H NMR (400 MHz, D₂O) δppm = 8.77 (s, 1H), 7.58 (br s, 1H), 6.92- 6.85 (m, 1H), 5.32 (br d, J =8.3 Hz, 1H), 4.78-4.77 (m, 1H, under D₂O), 4.61- 4.47 (m, 1H), 4.26 (brs, 3H), 3.46 (br s, 2H), 3.04 (br s, 2H), 2.98 (br d, J = 7.5 Hz, 1H),2.90 (s, 3H), 2.09 (br s, 1H)

435 LCMS [M + 1] (1S,2S,3S,5R)-3-((5,6- difluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(5-fluoro-2- methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol HCl Salt ¹H NMR (400 MHz, D₂O) δppm = 9.09 (s, 1H), 7.59 (s, 1H), 6.87 (br dd, J = 6.5, 12.3 Hz, 1H),5.39- 5.30 (m, 1H), 4.58-4.57 (m, 1H), 4.24 (br s, 2H), 3.63 (br d, J =5.0 Hz, 1H), 3.56 (s, 2H), 3.45 (br t, J = 5.8 Hz, 1H), 3.03 (br s, 2H),2.99-2.92 (m, 1H), 2.78 (s, 3H), 2.08 (br d, J = 10.5 Hz, 1H)

432 LCMS [M + 1] (1S,2S,3R,5S)-3-(4- amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-5-((5,6-difluoro- 1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2- diol HCl Salt ¹H NMR(400 MHz, MeOD-d4) δ ppm = 8.27 (s, 1H), 7.37 (s, 1H), 7.15- 7.00 (m,1H), 5.29-5.11 (m, 1H), 4.73-4.57 (m, 2H), 4.35 (br s, 2H), 4.17 (br d,J = 3.5 Hz, 1H), 3.61- 3.49 (m, 2H), 3.13 (br s, 2H), 3.02-2.91 (m, 1H),2.55-2.44 (m, 3H), 2.23- 2.09 (m, 1H)

Example 180 (SchemeTTT)—(1S,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(TTT-5)

Step 1: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-6-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(TTT-2)

Intermediate TTT-1 was prepared by following the general procedures forsteps 1-3 in Scheme SS employing TP-2 and5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as the appropriate startingmaterials.

To a scintillation vial, equipped with a magnetic stirbar and containingintermediate TTT-2 (281 mg, 0.470 mmol), was added DCM (5.0 mL),2,2-dimethoxypropane (0.58 mL, 4.70 mmol), and PPTS (11.8 mg, 0.047mmol). The reaction was stirred at rt for 23 hours. The solution wastransferred to a separatory funnel with DCM and washed with 2 portionshalf saturate brine. The organic phase was dried (MgSO₄), filtered, andconcentrated under vacuum to afford the title compound TTT-2 (266 mg,89%) as a white solid. LCMS [M+H]=637 observed. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.68 (s, 1H), 7.49 (br. s., 1H), 6.97-6.86 (m, 1H),6.84-6.71 (m, 1H), 5.35 (br. s., 1H), 4.95 (dd, J=2.1, 6.1 Hz, 1H), 4.81(d, J=6.1 Hz, 2H), 4.48 (br. s., 2H), 3.65 (br. s., 2H), 3.07-2.89 (m,1H), 2.80 (br. s., 2H), 2.50 (d, J=15.3 Hz, 1H), 1.60 (s, 3H), 1.47 (br.s., 9H), 1.34 (s, 3H).

Step 2: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-6-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(TTT-3)

To a microwave vial, equipped with a magnetic stirbar, was added TTT-2(152 mg, 0.238 mmol) as a solution in dioxane (0.60 mL). To the solutionwas added ammonium hydroxide (0.6 mL, 5.00 mmol) and the vial was sealedwith a Teflon cap. The vial was placed in a microwave reactor and heatedto 120 C for 6 hours then allowed to cool to rt overnight. The solutionwas transferred to a separatory funnel with DCM and diluted with water.The phases were separated and the aqueous phase was extracted with 3portions of DCM. The combined organic extracts were dried (MgSO₄),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (12g SiO₂, Isco, 100% Hept. to 100%EtOAc, 9 mL fractions) to afford the title compound TTT-3 (81 mg, 55%)as a white solid. LCMS [M+H]=618 observed.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 (s, 1H), 7.16 (s, 1H),6.98-6.85 (m, 1H), 6.84-6.73 (m, 1H), 5.61 (br. s., 2H), 5.36-5.18 (m,1H), 4.94 (dd, J=2.5, 6.1 Hz, 1H), 4.82-4.73 (m, 2H), 4.56-4.45 (m, 2H),3.90-3.42 (m, 2H), 3.02-2.87 (m, 1H), 2.80 (t, J=4.9 Hz, 2H), 2.46 (td,J=4.4, 14.8 Hz, 1H), 1.59 (s, 3H), 1.53-1.42 (m, 9H), 1.33 (s, 3H).

Step 3: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(TTT-4)

To a reaction vial, equipped with a magnetic stibar, was added TTT-3(81.0 mg, 0.131 mmol), potassium carbonate (54.3 mg, 0.393 mmol), andPd(PPh₃)₄(15.1 mg, 0.013 mmol). The vial was sealed with a teflon capand purged with argon under dynamic vacuum. To the vial was addeddioxane (0.58 mL) and water (0.07 mL). The vial was transferred to aheating block and heated at 100° C. for 3.5 days. The vial was removedfrom the heating block and allowed to cool to rt. The reaction wasdiluted with water and transferred to a separatory funnel with DCM. Thephases were separated and the aqueous phase was extracted with 3portions of DCM. The combined organic extracts were dried (MgSO₄),filtered, and concentrated under vacuum. The crude residue was purifiedvia preparative high performance liquid chromatography (Lux 5 uCellulose-2 30×250 mm column, 33% MeOH w/0.05% DEA in CO₂, 100 bar, 80mL/min) to afford the title compound TTT-4 (17.1 mg, 24%) as a whitesolid. LCMS [M+H]=540 observed. [α]D22=+2.2° (C=0.1, MeOH). ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.35 (s, 1H), 7.19 (d, J=3.7 Hz, 1H), 6.94-6.85(m, 1H), 6.84-6.75 (m, 1H), 6.44 (br. s., 1H), 5.34-5.26 (m, 1H), 5.19(br. s., 2H), 5.01 (dd, J=2.6, 6.2 Hz, 1H), 4.79 (d, J=6.4 Hz, 1H), 4.75(t, J=5.3 Hz, 1H), 4.44 (br. s., 2H), 3.65 (br. s., 2H), 3.07-2.86 (m,1H), 2.78 (t, J=5.1 Hz, 2H), 2.59-2.42 (m, 1H), 1.60 (s, 3H), 1.49 (br.s., 9H), 1.33 (s, 3H).

Step 4: Synthesis of(1S,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol(TTT-5)

To a scintillation vial, equipped with a magnetic stirbar and containingTTT-4 (17.1 mg, 0.032 mmol), was added water (0.08 mL). To the solutionwas added hydrochloric acid (0.4 mL, 4.0 M in dioxane, 2 mmol) and thereaction was stirred at rt for 15 hours. The solution was transferred toa separatory funnel with DCM, diluted with water, and neutralized withsat. NaHCO₃. The phases were separated and the aqueous phase wasextracted with 3 portions of a 3:1 mixture of DCM:IPA. The combinedorganic extracts were dried (MgSO4), filtered, and concentrated undervacuum. The material thus obtained was freeze-dried to afford the titlecompound TTT-5 (12.5 mg, >95%) as a white solid. LCMS [M+H]=400observed. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (s, 1H), 7.22 (d,J=3.7 Hz, 1H), 6.95-6.79 (m, 2H), 6.63 (d, J=3.7 Hz, 1H), 5.12 (q, J=8.6Hz, 1H), 4.69-4.61 (m, 1H), 4.57 (dd, J=4.8, 8.4 Hz, 1H), 4.16 (d, J=4.3Hz, 1H), 3.96 (br. s., 2H), 3.08 (t, J=5.1 Hz, 2H), 2.97 (ddd, J=7.3,9.3, 14.6 Hz, 1H), 2.76 (t, J=5.9 Hz, 2H), 2.04 (ddd, J=3.9, 8.4, 14.1Hz, 1H).

Example181—(1S,2S,3S,5R)-3-((3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol

Step 1—Synthesis of2-benzyl-6-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-2-ium bromide(UUU-2)

To a mixture of 3-methyl-2,7-naphthyridin-1(2H)-one UUU-1 (prepared in asimilar method in patent WO2002068393) (3.9 g, 21.85 mmol) in CH₃CN (50mL) was added BnBr (6.25 g, 36.5 mmol) at rt (25° C.). Then, the mixturewas heated at refluxed (85° C.) for 16 hours. The precipitate wascollected by filtration, washed with ethanol (30 mL) and dried in vacuoto obtain UUU-2 (4.8 g, 60%) as a yellow solid. LCMS [M-Br] 251; ¹H NMR(400 MHz, DMSO-d₆) δ ppm=12.57 (br s, 1H), 9.77 (s, 1H), 8.88 (d, J=6.8Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.55 (br d, J=6.8 Hz, 2H), 7.44 (br d,J=7.3 Hz, 3H), 6.70 (s, 1H), 5.86 (s, 2H), 2.40 (s, 3H)

Step 2—Synthesis of7-benzyl-3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1(2H)-one (UUU-3)

To a solution of compound UUU-2 (4.8 g, 14.49 mmol) in MeOH (50 mL) wasadded NaBH₄ (7.68 g, 203 mmol) in portions for 10 mins at 0° C. thenstirred at rt (25° C.) for 4 hours. The mixture was concentrated invacuo to remove the solvent. DCM (40 mL) was added and filtrated. Thefiltrate was concentrated in vacuo to get the crude product which waspurified by silica gel chromatography (MeOH/DCM=0-10%) to obtain UUU-3(2.65 g, 72%) as a yellow solid. LCMS [M+1] 255; ¹H NMR (400 MHz,DMSO-d₆) δ ppm=11.33 (br s, 1H), 7.42-7.32 (m, 4H), 7.30-7.24 (m, 1H),5.78 (s, 1H), 3.63 (s, 2H), 3.11 (s, 2H), 2.59 (br d, J=4.5 Hz, 2H),2.56 (br d, J=3.5 Hz, 2H), 2.10 (s, 3H)

Step 3—2-benzyl-8-bromo-6-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine(UUU-4)

To a solution of UUU-3 (2.15 g, 8.45 mmol) in CH₃CN (20 mL) and Ph₂O (40mL) at rt (25° C.). Then, POBr₃ (12.1 g, 42.3 mmol) was addedportion-wise and heated at refluxed (85° C.) under N₂ for 4 hours inwhich an orange solid began to form after 20 min. The precipitate wascollected by filtration, dissolved in water (20 mL), and neutralizedwith NaHCO₃ solution to pH 8. Then, the mixture was extracted with TBME(50 mL×2). The organic layer was washed with brine (25 mL×2), dried overNa₂SO₄, filtrated and concentrated in vacuo to get crude product whichwas purified by chromatography (silica gel EtOAc/Petroleum ether=0-40%)to obtain UUU-4 (1.55 g, 58%) as an orange solid. LCMS [M+1] 317; ¹H NMR(400 MHz, CDCl₃) δ ppm=7.40-7.32 (m, 4H), 7.32-7.28 (m, 1H), 6.87 (s,1H), 3.75 (s, 2H), 3.59 (s, 2H), 2.84-2.78 (m, 2H), 2.69-2.64 (m, 2H),2.47 (s, 3H)

Step 4—Synthesis of tert-butyl8-bromo-6-methyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (UUU-5)and tert-butyl8-chloro-6-methyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate(UUU-6)

To a solution of compound UUU-4 (1.30 g, 4.1 mmol) in DCM (15 mL) wasadded drop-wise 1-chloroethyl chloroformate (0.62 mL, 5.74 mmol) at rt(0° C.) for 1 min. Then, the mixture was warmed up to rt (20° C.)stirred for 10 mins and heated at refluxed (40° C.) for 2 hours. Themixture was concentrated in vacuo to remove the solvent. Then the solidwas dissolved in MeOH (15 mL) and heated at refluxed (63° C.) for 1.5hours. Then (Boc)₂O (1.07 g 4.92 mmol) and Et₃N (1.71 mL, 12.3 mmol)were added. The mixture was heated at (63° C.) for 16 hours. The mixturewas concentrated in vacuo to get crude product which was purified bychromatography (silica gel MeOH/DCM=0˜10%) to get product a mixture ofcompound UUU-5 and UUU-6 in a ˜1:1 ratio (872 mg) as a white solid andused directly in the next step. LCMS [M+1] 327 and 283.

Steps 5-7 were performed in a similar manner as steps 2-4 in Scheme GGGusing FFF-1.

Example 181

396 [M + 1] (1S,2S,3S,5R)-3-((3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2- diol ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.64 (s, 1H), 7.61 (d, J = 3.8 Hz, 1H), 6.72 (d, J = 3.8 Hz, 1H), 6.63(s, 1H), 5.26-5.21 (m, 1H), 5.12 (q, J = 8.7 Hz, 1H), 4.56 (dd, J = 4.9,8.4 Hz, 1H), 4.05 (br d, J = 2.3 Hz, 1H), 3.94-3.82 (m, 2H), 3.05 (br t,J = 5.9 Hz, 2H), 2.86 (ddd, J = 7.4, 9.6, 14.4 Hz, 1H), 2.72- 2.66 (m,2H), 2.64 (s, 3H), 2.31 (s, 3H), 1.92-1.78 (m, 1H)

Synthesis oftert-butyl-5-fluoro-8-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-31)

Step 1: Synthesis of methyl 2-(benzyloxy)-5-fluorobenzoate (VVV-2)

To a round bottom flask, equipped with a magnetic stirbar, was addedmethyl 5-fluoro-2-hydroxybenzoate VVV-1 (3.68 g, 21.6 mmol), potassiumcarbonate (10.5 g, 75.7 mmol), and acetone (108 mL). To the solution wasadded benzyl bromide (2.70 mL, 22.7 mmol) and the flask was fitted witha Findenser™. The flask was placed in a heating mantle and heated at 65°C. for 13 hours. The flask was removed from the heating block andallowed to cool to rt. The solids were filtered over a bed of celite andwashed with several portions of acetone. The filtrate was concentratedunder vacuum and transferred to a separatory funnel with EtOAc (˜100mL). The solution was washed with 2 portions of half sat. brine, dried(MgSO₄), filtered, and concentrated under vacuum to afford the titlecompound VVV-2 (5.64 g, >95% yield) as a white crystalline solid. Thismaterial was used in the next step without further purification. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.54 (dd, J=3.3, 8.7 Hz, 1H), 7.51-7.45(m, 2H), 7.44-7.36 (m, 2H), 7.36-7.29 (m, 1H), 7.14 (ddd, J=3.2, 7.5,9.1 Hz, 1H), 6.97 (dd, J=4.3, 9.0 Hz, 1H), 5.16 (s, 2H), 3.92 (s, 3H).¹⁹F NMR (376 MHz, CHLOROFORM-d) δ ppm −122.59 (s, 1F).

Step 2: Synthesis of 2-(benzyloxy)-5-fluoro-N-hydroxybenzamide (VVV-3)

To a round bottom flask, equipped with a magnetic stirbar and containingVVV-2 (5.64 g, 21.7 mmol), was added hydroxyl amine hydrochloride (4.52g, 65.0 mmol), potassium hydroxide (7.29 g, 130 mmol), and methanol (108mL). The flask was fitted with a Findenser™ and placed in a heatingmantle. The reaction was heated at 75° C. for 3.5 hours. The reactionwas removed from the heating mantle and allowed to gradually cool to rt.The solution was neutralized with acetic acid and concentrated undervacuum. The residue was transferred to a separatory funnel with EtOAcand diluted with water. The phases were separated and the aqueous phasewas extracted with 3 100 mL portions of EtOAc. The organic extracts weredried (MgSO₄), filtered, and concentrated under vacuum to afford thetitle compound VVV-3 (5.62 g, >95% yield) as a white solid. The materialwas used in the next step without further purification. LCMS [M+H]=262observed. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1H), 9.18 (d, J=1.5Hz, 1H), 7.47 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.35-7.27 (m,2H), 7.25 (dd, J=3.2, 8.3 Hz, 1H), 7.19-7.13 (m, 1H), 5.20 (s, 2H). ¹⁹FNMR (376 MHz, DMSO-d6) δ ppm −123.18 (s, 1F).

Step 3: Synthesis of 2-(benzyloxy)-5-fluoro-N-(pivaloyloxy)benzamide(VVV-4)

To a round bottom flask, equipped with a magnetic stir bar andcontaining VVV-3 (3.0 g, 11.5 mmol), was added THF (35 mL) and triethylamine (1.60 mL, 11.5 mmol) followed by the dropwise addition of pivaloylchloride (1.55 mL, 12.6 mmol). The reaction was stirred at rt for 30minutes. The reaction was transferred to a separatory funnel with EtOAc.The solution was washed with 2 portions 1 M HCl aq., 1 portion halfsaturate NaHCO₃, and 2 portions brine. The organic solution was thendried (MgSO₄), filtered, and concentrated under vacuum. The cruderesidue was purified via flash column chromatography (40 g SiO₂, Isco,100% Hept. to 100% EtOAc, 20 mL fractions) to afford the title compound(3.83 g, >95%) as a colorless oil solvated with EtOAc. The oil was takenup in DCM and diluted with Heptane followed by concentration undervacuum. The material obtained was further dried under high vacuumovernight to afford the title compound VVV-4 (3.59 g, 90%) as a whitesolid. LCMS [M+H]=346 observed. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm10.95 (s, 1H), 7.89 (dd, J=3.2, 9.1 Hz, 1H), 7.53-7.33 (m, 5H), 7.16(ddd, J=3.3, 7.2, 9.0 Hz, 1H), 7.00 (dd, J=4.1, 9.1 Hz, 1H), 5.27 (s,2H), 1.35 (s, 9H).

Step 4: Synthesis of8-(benzyloxy)-5-fluoro-4-methyl-3,4-dihydroisoquinolin-1 (2H)-one(VVV-5)

To a scintillation vial, equipped with a magnetic stirbar, was addedVVV-4 (500 mg, 1.45 mmol), cesium pivalate (678 mg, 2.90 mmol), and[Cp^(t)RhCl₂]₂(25.4 mg, 0.036 mmol). The contents of the vial weretransferred to a high pressure reactor and TFE (7.0 mL) was added. Thereactor was purged with nitrogen 3 times followed by 3 cycles of purgingwith propylene gas. The reaction was heated to 45° C. under 4 barpressure of propylene gas for 20 hours. The solution was transferred toa round bottom flask and concentrated under vacuum. The crude residuewas purified via flash column chromatography (24 g SiO₂, Isco, 100%Hept. to 100% EtOAc, 9 mL fractions) to afford the title compound VVV-5(270 mg, 65%, 93:7 r.r.) as a light pink solid. HSCQC and HOESY analysesare consistent with the assigned regioisomer. LCMS [M+H]=286 observed.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (d, J=7.5 Hz, 2H), 7.43-7.34(m, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 6.87 (dd,J=4.3, 9.0 Hz, 1H), 5.98 (d, J=3.7 Hz, 1H), 5.29-5.21 (m, 1H), 5.18-5.11(m, 1H), 3.70 (ddd, J=0.7, 4.0, 12.6 Hz, 1H), 3.38-3.28 (m, 1H), 3.23(ddd, J=1.5, 6.0, 12.6 Hz, 1H), 1.35 (d, J=7.0 Hz, 3H). ¹⁹F NMR (376MHz, CHLOROFORM-d) δ ppm −129.24 (s, 1F).

Step 5: Synthesis oftert-butyl-8-(benzyloxy)-5-fluoro-4-methyl-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate(VVV-6)

To a round bottom flask, equipped with a magnetic stirbar, was addedVVV-5 (100 mg, 0.350 mmol) as a solution in DMF (4.0 mL). The solutionwas cooled to 10° C. followed by the addition of (Boc)₂O (84.1 mg, 0.386mmol), DIPEA (92 μL, 0.526 mmol) and DMAP (2.1 mg, 0.017 mmol). Thereaction was allowed to stir at rt for 16 hours providing low conversionto desired product. The reaction was then heated at 50° C. for 24 hoursand then increased to 75° C. for an additional 24 hours in order toachieve complete consumption of starting material. The reaction wasdiluted with water and transferred to a separatory funnel with EtOAc.The phases were separated and the organic phase was washed with 1portion brine, dried (Ns₂SO₄), filtered, and concentrated under vacuum.The crude residue was purified via flash column chromatography (SiO₂, 1%EtOAc/Pet. Ether to 40% EtOAc/Pet. Ether) to afford the title compoundVVV-6 (100 mg, 74%) as a colorless gum. LCMS [M+H-Boc]=286 observed.

Step 6: Synthesis oftert-butyl-8-(benzyloxy)-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(VVV-7)

To a round bottom flask, equipped with a magnetic stir bar, was addedVVV-6 (100 mg, 0.259 mmol) as a solution in THF. The solution was cooledto 0° C. followed by the dropwise addition of BH₃.THF. Upon completionof the addition, the reaction was removed from the ice bath and heatedto 60° C. under nitrogen for 6 hours. At this stage the reaction wascooled to −10° C. and quenched by the careful dropwise addition of MeOH.The reaction was allowed to stir at −10° C. for 16 hours and thenconcentrated under vacuum. The crude residue was purified viapreparative thin layer chomatography (SiO₂, 20% EtOAc/Pet. Ether) toafford the title compound VVV-7 (35.0 mg, 36%) as a colorless gum. LCMS[M+H-Isobutylene]=316 observed.

Step 7: Synthesis oftert-butyl-5-fluoro-8-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-31)

To a round bottom flask, equipped with a magnetic stirbar, was addedVVV-7 (70 mg, 0.190 mmol) as a solution in MeOH (4.5 mL). To thesolution was added Pd/C (10.0 mg, 0.094 mmol) and the headspace of theflask was purged with hydrogen 5 times. The reaction was allowed to stirat rt under 1 atm hydrogen gas for 2.5 hours. The reaction was filteredand the solids were washed with DCM. The filtrate was concentrated undervacuum and the crude residue was purified via preparative thin layerchromatography (SiO₂, 20% EtOAc/Pet. Ether) to afford the title compoundTP-31 (45 mg, 85%) as a colorless gum. LCMS [M+H-Isobutylene]=226observed. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.76 (br t, J=8.8 Hz,1H), 6.55 (dd, J=4.4, 8.7 Hz, 1H), 5.14-4.78 (m, 2H), 4.22-3.95 (m, 2H),3.23-2.94 (m, 2H), 1.54-1.46 (s, 9H), 1.23 (d, J=7.3 Hz, 3H).

Synthesis of tert-butyl(8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (TP-32)

Step 1—Synthesis of 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine(WWW-2)

To a stirred yellow suspension of8-methoxy-3,4-dihydronaphthalen-1(2H)-one WWW-1 (600 mg, 3.4 mmol) inMeOH (30 mL) was added CH₃COONH₄ (5.25 g, 68 mmol) at 15° C. The mixturewas stirred at 15° C. for 15 min and then, NaBH₃CN (1.5 g, 24 mmol) wasadded at 15° C. The mixture was irradiated in a microwave reactor at 60°C. for 45 min. The mixture was quenched by sat.NaHCO₃ (15 mL) and H₂O(15 mL) and stirred at 15° C. for 5 min. The mixture was concentrated toremove MeOH. The residue was extracted with DCM (20 mL×2). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give crude WWW-2 (580 mg, 96%) as a slightpink gum and used as is in the next step.

Step 2—Synthesis of 8-amino-5,6,7,8-tetrahydronaphthalen-1-ol (WWW-3)

Compound WWW-2 (550 mg, 3.10 mmol) was dissolved in HCl/dioxane (5.00mL), the solution was stirred at 15° C. for 10 min. Then the solutionwas evaporated to give a residue. The residue was dissolved in DCM andcooled to 0° C. on an ice bath. Then BBr₃ (7.77 mg, 31.0 mmol) was addedto the reaction solution dropwise. The reaction solution was stirred at20° C. for 5 hrs. The reaction solution was quenched with MeOH (8.00mL), then the pH of the solution was adjusted to pH=7 by the addition ofsaturated aq NaHCO₃. The final solution of WWW-3 was used for the nextstep directly (100 mL).

Step 3—Synthesis of tert-butyl(8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (TP-32)

To a solution of (Boc)₂O (730 mg, 3.34 mmol) in dioxane (5.00 mL) wasadded the solution of compound WWW-3 (solution in aq. sat. NaHCO₃, 15 mL˜3.3 mmol) at 0° C. in one portion. The reaction solution was stirred at20° C. for 50 hours. The reaction was extracted with DCM (2×) and theorganics combined and washed with sat. citric acid (2×15 mL), aq sat.Na₂CO₃ (2×15 mL), and brine (2×15 mL). The organics were dried andevaporated to give a residue which was purified by prep-TLC (PetroleumEther/EtOAc=4/1) to give TP-32 (410 mg, 50%) as a white solid. LCMS[M-tBu+1] 207; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.20 (s, 1H), 6.96 (t,J=7.8 Hz, 1H), 6.78 (br d, J=7.5 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 6.51(d, J=7.4 Hz, 1H), 4.80-4.71 (m, 1H), 2.72-2.63 (m, 1H), 2.61-2.53 (m,1H), 1.89-1.74 (m, 2H), 1.67-1.46 (m, 2H), 1.39 (s, 9H)

Synthesis of tert-butyl (5-hydroxychroman-3-yl)carbamate (TP-33)

Step 1—Synthesis of 5-(benzyloxy)chroman-3-amine (XXX-2)

Compound XXX-1 (700 mg, 2.73 mmol, prepared using exact procedures inliterature J. Org. Chem, 2013, 78, 7859-7884) was introduced to similarMitsunobu and Staudinger procedures in the same reference to give theproduct XXX-2 (520 mg, 75%) as a colorless gum, used in the next stepdirectly. LCMS [M+1] 266; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.48-7.36 (m,4H), 7.36-7.30 (m, 1H), 7.07 (t, J=8.3 Hz, 1H), 6.52 (dd, J=2.5, 8.3 Hz,2H), 5.07 (s, 2H), 4.18-4.07 (m, 1H), 3.80 (ddd, J=1.0, 7.3, 10.5 Hz,1H), 3.43-3.29 (m, 1H), 3.07 (dd, J=5.0, 16.6 Hz, 1H), 2.50 (dd, J=7.3,16.8 Hz, 1H)

Step 2—Synthesis of tert-butyl (5-(benzyloxy)chroman-3-yl)carbamate(XXX-3)

To a solution of XXX-2 (520 mg, 2.04 mmol) in dry MeOH (20 mL) was addedBoc₂O (889 mg, 4.07 mmol) at rt and stirred for 30 min (20 mL of EtOAcadded for solubility). The mixture was concentrated in vacuo to affordcrude material which was purified by silica gel chromatography elutedwith EtOAc in petroleum ether from 0 to 50% then EtOAc in DCM from 0 to50% to afford XXX-3 (620 mg, 76%) as white solid. LCMS [M-tBu+1] 300; ¹HNMR (400 MHz, CDCl₃) δ ppm 7.45-7.36 (m, 4H), 7.34 (br d, J=6.8 Hz, 1H),7.12-7.05 (m, 1H), 6.53 (d, J=8.3 Hz, 2H), 5.06 (s, 2H), 4.91-4.79 (m,1H), 4.26-4.15 (m, 1H), 4.08 (br s, 2H), 3.01-2.92 (m, 1H), 2.81-2.69(m, 1H), 1.44 (s, 9H)

Step 3—Synthesis of tert-butyl (5-hydroxychroman-3-yl)carbamate (TP-33)

A mixture of XXX-3 (620 mg, 2.43 mmol) and Pd/C (300 mg) in MeOH/EtOAc(10 mL/10 mL) was degassed with H₂ four times. The mixture was stirredat rt under an H₂ balloon for 16 hrs. The mixture was filtered andconcentrated. (Excess Boc₂O from the previous step also Boc-protectedthe phenol, therefore MeOH (20 mL) and K₂CO₃ (2 g) were added andstirred for 2 h, then filtered). The mixture was filtered andconcentrated. The crude material was diluted with EtOAc and was washedwith brine (15 mL), dried over Na₂SO₄ and concentrated in vacuo thenlyophilized to afford TP-33 (420 mg, 91%) as a white solid. LCMS[M-tBu+1] 210; ¹H NMR (400 MHz, CDCl₃) δ ppm 6.99 (t, J=8.2 Hz, 1H),6.48 (d, J=8.3 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 5.19 (br s, 1H),4.96-4.89 (m, 1H), 4.22 (br s, 1H), 4.15-4.03 (m, 2H), 2.91 (dd, J=5.5,16.8 Hz, 1H), 2.71 (br d, J=17.3 Hz, 1H), 1.45 (s, 9H)

Example 182 and Example 183 (SchemeYYY)—(1S,2S,3S,5R)-3-((-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diolhydrochloride (YYY-3-isomer 1 and YYY-3-isomer 2)

Step 1: Synthesis oftert-butyl-5-fluoro-4-methyl-8-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(YYY-1)

To a microwave vial, equipped with a magnetic stirbar, was added TP-31(45 mg, 0.160 mmol), BB-2 (50.4 mg, 0.160 mmol), Pd₂(dba)₃′CHCl₃ (4.14mg, 0.004 mmol), DPPP (3.96 mg, 0.010 mmol), and cesium carbonate (57.3mg, 0.176 mmol). The vial was purged with nitrogen under dynamic vacuumand freshly degassed DCE (1.0 mL) was added. The solution was stirred atrt under nitrogen for 1 hour. The solution was concentrated under vacuumand the crude residue was purified via preparative thin layerchromatography (SiO₂, 33% EtOAc/Pet. Ether) to afford the title compoundYYY-1 (60 mg, 86%) as a gum. LCMS [M+H]=579 observed. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.76 (s, 1H), 7.35-7.28 (m, 1H), 6.84 (br t, J=8.7Hz, 1H), 6.73-6.51 (m, 2H), 6.37 (br s, 1H), 6.19-5.99 (m, 2H), 5.28 (brs, 1H), 4.24-3.95 (m, 2H), 3.22-3.05 (m, 3H), 2.73 (d, J=2.5 Hz, 3H),1.96 (brd, J=14.6 Hz, 1H), 1.69-1.63 (m, 1H), 1.50 (s, 9H), 1.23 (t,J=7.0 Hz, 3H)

Step 2: Synthesis oftert-butyl-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(YYY-2)

To a reaction vial, equipped with a magnetic stirbar, was added YYY-1(60.0 mg, 0.130 mmol) as a solution in DCM (6.0 mL). To the solution wasadded water (0.2 mL), NMO (44.1 mg, 0.376 mmol) and OsO₄ (112 mg, 0.0176mmol). The reaction was allowed to stir at rt for 5 hours. The reactionwas quenched with sat. Na₂SO₃ (5 mL) and transferred to a separatoryfunnel with DCM. The phases were separated and the aqueous phase wasextracted with 1 portion DCM. The combined organic extracts were dried(Na₂SO₄), filtered, and concentrated under vacuum. The crude residue waspurified via preparative thin layer chromatography to afford the titlecompound YYY-2 (35 mg, 54%) as a colorless gum. LCMS [M+H]=513 observed.

Step 3: Synthesis oftert-butyl-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(YYY-2-isomer 1 & YYY-2-isomer 2)

YYY-2 (30 mg, 0.058 mmol) was further purified via preparativesuper-critical fluid chromatography (OD 250 mm×30 mm×5 μm, 0.1%NH₄OH/IPA to 30% NH₄OH/IPA, 60 mL/min) to afford the separateddiastereomers YYY-2-isomer 1 (15 mg, 50%) and YYY-2-isomer 2 (15 mg,50%) as white solids. LCMS [M+H]=513 observed.

Step 4 employing YYY-2-isomer 1: Synthesis of(1S,2S,3S,5R)-3-((-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diolhydrochloride (YYY-3-isomer 1)

To a reaction vial, equipped with a magnetic stirbar, was addedYYY-2-isomer 1 (15 mg, 0.029 mmol) as a solution in EtOAc (1.0 mL). Thesolution was cooled to 0° C. followed by the addition of HCl (4M EtOAc,59 μL). The reaction was removed from the ice bath and stirred at rt for16 hours. The solution was concentrated under vacuum followed byfree-drying to afford the title compound YYY-3-isomer 1 (8.26 mg, 63%)as a white solid. LCMS [M+H]=413 observed. ¹H NMR (400 MHz, METHANOL-d4)δ ppm 9.05 (d, J=3.3 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.24 (d, J=3.7 Hz,1H), 7.15-6.99 (m, 2H), 5.41 (q, J=9.3 Hz, 1H), 4.76 (br d, J=4.8 Hz,2H), 4.52-4.41 (m, 1H), 4.36-4.27 (m, 1H), 4.23 (d, J=4.8 Hz, 1H),3.57-3.40 (m, 3H), 3.12-2.99 (m, 4H), 2.27 (dt, J=5.1, 9.5 Hz, 1H), 1.47(d, J=6.7 Hz, 3H).

Step 4 employing YYY-2-isomer 2: Synthesis of(1S,2S,3S,5R)-3-((-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diolhydrochloride (YYY-3-isomer 2))

To a reaction vial, equipped with a magnetic stirbar, was addedYYY-2-isomer 2 (15 mg, 0.029 mmol) as a solution in EtOAc (1.0 mL). Thesolution was cooled to 0° C. followed by the addition of HCl (4M EtOAc,59 μL). The reaction was removed from the ice bath and stirred at rt for16 hours. The solution was concentrated under vacuum followed byfree-drying to afford the title compound YYY-2-isomer 2 (8.48 mg, 70%)as a white solid. LCMS [M+H]=413 observed. ¹H NMR (400 MHz, METHANOL-d4)δ ppm 9.04 (d, J=3.0 Hz, 1H), 8.06 (d, J=3.2 Hz, 1H), 7.24 (d, J=3.7 Hz,1H), 7.16-7.01 (m, 2H), 5.42 (q, J=9.4 Hz, 1H), 4.77-4.70 (m, 2H),4.48-4.39 (m, 1H), 4.36-4.27 (m, 1H), 4.21 (d, J=4.7 Hz, 1H), 3.55-3.40(m, 3H), 3.17-2.96 (m, 4H), 2.33-2.18 (m, 1H), 1.46 (d, J=6.7 Hz, 3H).

Examples 184-189 were made in a similar fashion as Examples 182 & 183(Scheme YYY) starting with the appropriate racemictetrahydroisoquinoline in step 1 and separating the diastereomers priorto the final deprotection.

395 LCMS [M + 1] (1S,2S,3S,5R)-3-((3-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol Example184 (Isomer 1)-¹H NMR (400 MHz, METHANOL-d4) δ ppm 9.07 (s, 1H), 8.08(d, J = 3.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 3.8 Hz, 1H),7.01 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.42 (q, J = 9.2 Hz,1H), 4.83-4.73 (m, 2H), 4.54 (d, J = 16.3 Hz, 1H), 4.34 (d, J = 16.6 Hz,1H), 4.24 (d, J = 4.5 Hz, 1H), 3.73-3.62 (m, 1H), 3.23-3.04 (m, 2H),3.03-2.91 (m, 4H), 2.32- 2.23 (m, 1H), 1.54 (d, J = 6.5 Hz, 3H). Example185 (Isomer 2)-¹H NMR (400 MHz, METHANOL-d4) 9.08 (s, 1H), 8.06 (d, J =3.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 7.01(d, J = 8.3 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 5.41 (q, J = 9.2 Hz, 1H),4.84-4.73 (m, 2H), 4.59-4.50 (m, 1H), 4.34 (d, J = 16.8 Hz, 1H), 4.22(d, J = 5.0 Hz, 1H), 3.70-3.60 (m, 1H), 3.21-3.05 (m, 2H), 3.04- 2.92(m, 4H), 2.34-2.25 (m, 1H), 1.55 (d, J = 6.3 Hz, 3H)

378 LCMS [M − 16 + 1] (1S,2S,3S,5R)-3-((8-amino-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2- diol Example 186 (Isomer 1)-¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.71 (s, 1H), 7.74 (d, J = 3.8 Hz, 1H), 7.34(t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H),6.86 (d, J = 3.5 Hz, 1H), 5.18 (q, J = 9.4 Hz, 1H), 4.84-4.79 (m, 3H),4.22 (d, J = 5.3 Hz, 1H), 3.06 (td, J = 8.4, 14.3 Hz, 1H), 2.98-2.88 (m,1H), 2.88- 2.81 (m, 1H), 2.80 (s, 3H), 2.50 (ddd, J = 4.3, 10.0, 14.1Hz, 1H), 2.25-2.10 (m, 2H), 1.98-1.89 (m, 2H) Example 187 (Isomer 2)-¹HNMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.53 (d, J = 3.5 Hz, 1H),7.15 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.78-6.72 (m, 2H),5.18 (q, J = 9.1 Hz, 1H), 4.82 (dd, J = 5.0, 8.5 Hz, 1H), 4.78-4.72 (m,1H), 4.40- 4.29 (m, 2H), 3.04-2.93 (m, 1H), 2.89-2.74 (m, 2H), 2.73 (s,3H), 2.36-2.23 (m, 1H), 2.02-1.86 (m, 3H), 1.80 (d, J = 4.5 Hz, 1H)

397 LCMS [M + 1] (1S,2S,3S,5R)-3-((3- aminochroman-5-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol Example188 (Isomer 1)-¹H NMR (400 MHz, D₂O) δ ppm 8.82 (s, 1H), 7.81 (d, J =3.8 Hz, 1H), 7.15 (t, J = 8.3 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 6.65(d, J = 7.8 Hz, 1H), 6.56 (d, J = 8.3 Hz, 1H), 5.33 (q, J = 9.1 Hz, 1H),4.77-4.73 (m, 1H), 4.62 (dd, J = 5.1, 8.7 Hz, 1H), 4.32-4.22 (m, 2H),4.14 (d, J = 11.3 Hz, 1H), 3.97 (br d, J = 1.8 Hz, 1H), 3.13 (dd, J =6.3, 18.1 Hz, 1H), 3.02 (ddd, J = 7.0, 9.8, 15.1 Hz, 1H), 2.87 (m, 4H),2.21-2.12 (m, 1H) Example 189 (Isomer 2)-¹H NMR (400 MHz, D₂O) δ ppm8.84 (s, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H), 7.10(d, J = 3.8 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H),5.41-5.31 (m, 1H), 4.77 (br s, 2H), 4.36-4.28 (m, 2H), 4.17 (br d, J =12.0 Hz, 1H), 4.01 (br d, J = 1.5 Hz, 1H), 3.20-3.10 (m, 1H), 3.09-2.99(m, 1H), 2.94 (br s, 1H), 2.90 (s, 3H), 2.23-2.12 (m, 1H)

Example 190 (SchemeZZZ)—(1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(ZZZ-16)

Step 1—Synthesis of methyl 4-bromo-5-fluoro-2-methoxybenzoate (ZZZ-2)

A solution of 4-bromo-2,5-difluorobenzoic acid ZZZ-1 (95 g, 400.85 mmol)in 4M HCl/MeOH (1500 mL) was heated at 65° C. for 3 hours. The mixturewas concentrated in vacuum to get ZZZ-2 (100 g, >99%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.93 (dd, J=5.5, 9.8 Hz, 1H),7.81 (dd, J=6.0, 8.5 Hz, 1H), 3.92-3.85 (m, 3H)

Step 2—Synthesis of 4-bromo-5-fluoro-2-methoxybenzoic acid (ZZZ-3)

To a solution of ZZZ-2 (80 g, 7.97 mmol) in dry DMF (1200 mL) was addeda solution MeONa (˜17.2 g, 319 mmol, 8 g Na dissolved in 80 mL MeOHobtained) at 0° C. The mixture was stirred at 0° C. for 10 mins, thenwarmed up to rt (25° C.) and stirred for 1 h. To the mixture was addedTBME (1 L) then, poured into ice water (800 mL). The mixture wasextracted with TBME (500 mL×4). The organic layer was washed with brine(300 mL×2) dried over Na₂SO₄, filtered and concentrated to get productthe methyl ether, methyl ester (12.1 g) as light yellow gum. The aqueouslayer contained the carboxylic acid and was neutralized with HCl (1M) topH=5 then, extracted with EtOAc (800 mL×3). The organic layer was washedwith brine (400 mL×2), dried over Na₂SO₄, filtered and concentrated toobtain ZZZ-3 (100g, >99% crude) as a yellow oil and used directly in thenext step. NMR contained DMF. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.59 (d,J=8.8 Hz, 1H), 7.46 (d, J=5.8 Hz, 1H), 3.83 (s, 3H)

Step 3—Synthesis of 4-bromo-5-fluoro-2-hydroxybenzoic acid (ZZZ-4)

To a solution of ZZZ-3 (˜60g crude, 240.93 mmol) in dry DCM (600 mL) wasadded BBr₃ (68.3 mL dissolved in DCM 600 mL, 723 mmol) at rt (20° C.).The mixture was stirred at rt (20° C.) for 2 h. The mixture was pouredwater (500 mL) and extracted with DCM (800 mL×3). The organic layer waswashed with brine (300 mL×2) dried over Na₂SO₄ filtered and concentratedto obtain ZZZ-4 (35 g, 62%) as a yellow gum. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.62 (d, J=9.0 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H)

Step 4—Synthesis of benzyl 2-(benzyloxy)-4-bromo-5-fluorobenzoate(ZZZ-5)

To a solution of ZZZ-4 (35 g, 148.93 mmol) in dry DMF (300 mL) was addedK₂CO₃ (41.2 g, 298 mmol) and BnBr (38.2 g, 223 mmol). The mixture wasstirred at 25° C. for 16 hrs. The mixture was diluted with water (200mL) and extracted with EtOAc (300 mL×3). The organic layers werecollected, dried and concentrated to give a crude light yellow oil whichwas purified by combi-flash (silica gel EtOAc/Petroleum ether=0-8%) toobtain ZZZ-5 (22 g, 36%) as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.67 (d, J=8.6 Hz, 1H), 7.48-7.32 (m, 10H), 7.25 (d, J=5.5Hz, 1H), 5.36 (s, 2H), 5.14 (s, 2H)

Step 5—Synthesis of 2-(benzyloxy)-4-bromo-5-fluorobenzoic acid (ZZZ-6)

To a solution of ZZZ-5 (22 g, 52.98 mmol) in MeOH (200 mL) was added asolution of LiOH.H₂O (6.67 g, 159 mmol) in H₂O (200 mL). The reactionmixture was stirred at 20° C. for 4 hours. The reaction mixture wasextracted with EtOAc (150 mL×2). The water layer was neutralized with 1M aq. HCl at 0° C. to pH 4-5, then extracted with EtOAc (200 mL×2). Theorganic layer was washed with brine (50 mL×2) dried over Na₂SO₄,filtered and concentrated to obtain ZZZ-6 (12.5 g, 73%) as a whitesolid. LCMS [M+1] 324.96; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (br s,1H), 7.66-7.56 (m, 2H), 7.53-7.46 (m, 2H), 7.45-7.37 (m, 1H), 7.45-7.37(m, 1H), 7.37-7.30 (m, 1H), 5.22 (s, 2H)

Step 6—Synthesis of2-(benzyloxy)-4-bromo-5-fluoro-N-(pivaloyloxy)benzamide (ZZZ-7)

To a solution of ZZZ-6 (23 g, 70.74 mmol) in THF (300 mL) was addedO-pivaloylhydroxylamine (35.4 g, 141 mmol), DIPEA (54.9 g, 424 mmol) atrt (25° C.). Then T3P (113 g, 177 mmol) was added at 0° C. Afteraddition the mixture was stirred 0° C. for 10 mins then, warmed up to rt(20° C.) and stirred for 16 hours. The mixture was concentrated toremove most of the solvent. The remaining mixture was diluted with EtOAc(80 mL), washed with sat. aq NaHCO₃ (50 mL) and extracted with EtOAc(100 mL×2). The organic layer was washed with brine (50 mL×2) dried overNa₂SO₄, filtered and concentrated to give the crude product (42 g) as ayellow gum which was purified by chromatography (silica gel,EtOAc/Petroleum ether=0-25%) to afford ZZZ-7 (26 g, 87%) as a lightyellow solid. LCMS [M+1] 424; ¹H NMR (400 MHz, CDCl₃) δ ppm 10.80 (br s,1H), 7.93 (d, J=8.8 Hz, 1H), 7.51-7.34 (m, 5H), 7.27-7.23 (m, 1H), 5.24(s, 2H), 1.33 (s, 9H)

Step 7—Synthesis of8-(benzyloxy)-6-bromo-5-fluoro-3,4-dihydroisoquinolin-1(2H)-one (ZZZ-8)

To a suspension of ZZZ-7 (26g, 64 mmol) in MeCN (600 mL) was added KOAc(6.91g, 70.4 mmol) and [Cp*Rh₂Cl₂]₂(2.37 g, 3.84 mmol) in vessel wascooled to 0° C. in which ethylene was purged into the vessel for 30 minsand sealed. The reaction was stirred at rt (20° C.) for 16 hours. Themixture was concentrated to give crude product (26 g) as a yellow solidwhich was purified by chromatography (silica gel petroleumether:EtOAc=0-100%) to obtain ZZZ-8 (12 g, 59%) as a yellow solid. LCMS[M+1] 351; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.92 (br s, 1H), 7.56 (d,J=7.0 Hz, 2H), 7.44-7.35 (m, 3H), 7.34-7.28 (m, 1H), 5.19 (s, 2H), 3.30(dt, J=3.6, 6.2 Hz, 2H), 2.86 (t, J=6.1 Hz, 2H)

Step 8—Synthesis of tert-butyl8-(benzyloxy)-6-bromo-5-fluoro-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-9)

To a solution of ZZZ-8 (11 g, 33.113 mmol) in THF (40 mL) and DCM (120mL) was added Boc₂O (11.6 g, 53 mmol), DIPEA (15 g, 116 mmol) and DMAP(607 mg, 4.97 mmol). After the addition, the mixture was stirred at rt(22° C.) for 16 hours. The reaction was concentrated to get the crudematerial (17.2 g,) as a yellow gum which was then purified bycombi-flash (EtOAc/petroleum ether=0-20%) to obtain ZZZ-9 (14.52 g, 97%)as a light yellow solid. LCMS [M+23] 472; ¹H NMR (400 MHz, DMSO-d₆) δppm 7.63-7.22 (m, 6H), 5.32-5.14 (m, 2H), 3.86 (t, J=6.0 Hz, 2H), 2.97(t, J=5.9 Hz, 2H), 1.50 (s, 9H)

Step 9—Synthesis of tert-butyl8-(benzyloxy)-6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-10)

To a solution of ZZZ-9 (14.81 g, 32.9 mmol) in THF (150 mL) was addedBH₃Me₂S (19.7 mL, 197 mmol) at rt (25° C.). The mixture was heated at70° C. for 1 hour. The reaction was quenched with MeOH (40 mL) slowly.The mixture was refluxed (65° C.) for 16 hs. The mixture wasconcentrated to give the crude product (26 g) as a yellow gum in whichwater (60 mL) was added the product extracted with EtOAc (100 mL×2). Theorganic layer was washed with brine (50 mL×2) dried over Na₂SO₄filtrated and concentrated to get crude material (17 g) which waspurified by chromatography (silica gel, EtOAc/petroleum ether=0-25%) toafford ZZZ-10 (13.2 g) as a light yellow gum which was lyophilized toget ZZZ-10 (13.06 g, 91%) was obtained as a white solid. LCMS [M-Boc+1]337; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.44-7.31 (m, 5H), 6.92 (d, J=5.5 Hz,1H), 5.04 (br s, 2H), 4.51 (s, 2H), 3.63 (br t, J=5.8 Hz, 2H), 2.88-2.72(m, 2H), 1.50 (s, 9H)

Step 10—Synthesis of tert-butyl8-(benzyloxy)-5-fluoro-6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-11)

In an oven dried round bottom flask was added ZZZ-10 (285 mg, 0.653mmol) and dry THF (4.35 mL, 0.15 M). A solution of DMF (0.98 mL, 0.98mmol, 1M in THF) was added to and the mixture was cooled to −78° C. withdry ice/acetone. nBuLi (0.92 mL, 1.47 mmol, 1.6M in hexanes) was addeddrop-wise and stirred at −78° C. for 30 min in which the reaction turnedfrom clear to yellow. LCMS still showed ˜50% of ZZZ-10 and thereforeanother 0.5 eq of DMF (0.49 mL, 0.49 mmol, 1M in THF) and nBuLi (0.46mL, 0.735 mmol, 1M in hexanes) were added and stirred for 25 min. Thereaction was quenched with water and extracted with EtOAc. The aqueouslayer was extracted with EtOAc 3×. The combined organics were washedwith water and dried over Na₂SO₄, filtered and concentrated to a crudeyellow oil (404 mg) which was purified by ISCO 25g 0-20% EtOAc/Heptanesto afford ZZZ-11 as a clear oil (215 mg, 60%).

LCMS [M+1] 286; ¹H NMR (400 MHz, CDCl₃) δ ppm 10.35 (s, 1H), 7.49-7.32(m, 5H), 7.23 (d, J=5.3 Hz, 1H), 5.13 (br. s., 2H), 4.64 (s, 2H), 3.69(t, J=5.7 Hz, 2H), 2.86 (t, J=5.1 Hz, 2H), 1.52 (s, 9H)

Step 11—Synthesis of tert-butyl8-(benzyloxy)-6-(difluoromethyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-12)

To a solution of ZZZ-11 (418 mg, 1.08 mmol) was added DCM (10.8 mL,0.1M). The solution was cooled to 0° C. then DAST (0.36 mL, 2.71 mmol)was added drop-wise and stirred for 4 h at r.t. LCMS shows ˜25% ofproduct. The reaction was cooled down to 0° C. and DAST was re-addeddrop-wise (0.36 mL, 2.71 mmol) and stirred at r.t. for 2 hours. Thereaction was not complete and an additional 2 eq was added and stirredfor 2 h. The reaction was then neutralized with sat. aq. NaHCO₃. Thelayers were separated and the aqueous layer was extracted with DCM 2×,dried over Na₂SO₄, filtered and concentrated then purified by ISCO 12g0-15% EtOAc/Heptanes to afford ZZZ-12 as a white solid (322 mg, 73%).LCMS [M-Boc+1]308; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.47-7.32 (m, 5H),7.03-6.75 (m, 2H), 5.10 (br. s., 2H), 4.59 (br. s., 2H), 3.66 (t, J=5.6Hz, 2H), 2.84-2.75 (m, 2H), 1.50 (s, 9H)

Step 12—Synthesis of tert-butyl6-(difluoromethyl)-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-13)

In round bottom flask was added ZZZ-12 (322 mg, 0.79 mmol) and MeOH(15.8 mL, 0.05 M). 10% Pd/C (30 mg) was added and a hydrogen balloon wasadded. The reaction was stirred at r.t. overnight. The reaction wasfiltered with a syringe and filter tip. The crude white material (252mg) was dissolved in DCM:MeOH (˜2:1) for complete solubility to addedinto an ISCO 12g and purified with 0-25% EtOAc/heptanes to give ZZZ-13as a white solid (239 mg, 95%). LCMS [M-Boc+1] 218; ¹H NMR (400 MHz,CDCl₃) δ ppm 6.99-6.62 (m, 2H), 4.55 (br. s., 2H), 3.66 (t, J=5.9 Hz,2H), 2.79 (br. s., 2H), 1.52 (s, 9H)

Step 13—Synthesis of tert-butyl6-(difluoromethyl)-5-fluoro-8-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-14)

To a microwave vial (which was dried with heat gun, then cooled under astream of N₂) was added compound BB-2 (238 mg, 0.753 mmol), ZZZ-13 (239mg, 0.753 mmol), Cs₂CO₃ (270 mg, 0.829 mmol), DPPP (18.7 mg, 0.0452mmol) and Pd₂(dba)₃-CHCl₃ (19.5 mg, 0.02 mmol), the vial was purged withN₂ for five and DCE (3 mL, sparged with N₂ for 30 mins) was added. Thevial was purged with N₂ three more times. The solution was stirred at18° C. under N₂ for 55 min.

The reaction mixture was purified by prep-TLC (EtOAc/petroleumether=1.5:1) to give product ZZZ-14 (330 mg, 85%) as a colorless gum.LCMS [M+1] 515; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.78 (s, 1H), 7.29 (br d,J=3.4 Hz, 1H), 7.04-6.72 (m, 2H), 6.59 (br d, J=3.0 Hz, 1H), 6.39 (br d,J=5.3 Hz, 1H), 6.19 (br d, J=4.6 Hz, 1H), 6.08 (br dd, J=2.2, 4.3 Hz,1H), 5.40-5.32 (m, 1H), 4.50 (br s, 2H), 3.73-3.57 (m, 2H), 3.26-3.16(m, 1H), 2.80 (br t, J=5.4 Hz, 2H), 2.74 (s, 3H), 1.52 (s, 9H)

Step 14—Synthesis of tert-butyl6-(difluoromethyl)-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(ZZZ-15)

To a mixture of ZZZ-14 (330 mg, 0.641 mmol) in DCM (10 mL)/H₂O (0.4 mL)was added NMO (225 mg, 1.92 mmol) and OsO₄ (4% in t-BuOH, 285 mg, 0.045mmol) at 15° C. The black solution was stirred at 18° C. for 3 hours.The mixture was quenched with sat. aq. Na₂SO₃ (5 mL) and diluted withDCM (10 mL) and separated. The aqueous layer was extracted with DCM (5mL). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated to yield crude product (450 mg)as a brown solid, which was purified by prep-TLC (first,EtOAc/MeOH=20:1, second, EtOAc) to afford ZZZ-15 (210 mg, 60%) as alight yellow solid. LCMS [M+1] 549; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.69(s, 1H), 7.22 (d, J=3.8 Hz, 1H), 7.10 (br d, J=5.3 Hz, 1H), 7.04-6.73(m, 1H), 6.61 (d, J=3.8 Hz, 1H), 5.03-4.88 (m, 1H), 4.80 (br s, 1H),4.60-4.39 (m, 3H), 4.36-4.24 (m, 1H), 3.65 (br d, J=5.8 Hz, 2H),3.46-3.29 (m, 1H), 3.20-3.02 (m, 1H), 2.80 (br t, J=5.4 Hz, 2H), 2.74(s, 3H), 2.62 (s, 1H), 2.39 (s, 1H), 1.56-1.34 (m, 9H)

Step 15—Synthesis of(1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol(ZZZ-16)

To a solution of ZZZ-15 (210 mg, 0.383 mmol) in DCM (2 mL) was added HCl(g)/dioxane (4 N, 0.766 mL, 3.06 mmol) at 0θ° C. The mixture was stirredat 23° C. for 2 hours. Solid was precipitated. The solvent was decantedand the solid dried and lyophilized lyophilized to give ZZZ-16 as 2HClsalt+2H₂O (165 mg, 83%) as a light yellow solid. LCMS [M+1] 449; ¹H NMR(400 MHz, D₂O) δ ppm 8.93 (s, 1H), 7.91 (d, J=3.8 Hz, 1H), 7.24-6.88 (m,3H), 5.41 (q, J=9.0 Hz, 1H), 4.87 (br dd, J=2.4, 4.4 Hz, 1H), 4.75 (dd,J=5.0, 8.8 Hz, 1H), 4.45 (s, 2H), 4.39 (br d, J=5.0 Hz, 1H), 3.58 (t,J=6.3 Hz, 2H), 3.19-3.07 (m, 3H), 2.99 (s, 3H), 2.35-2.24 (m, 1H).

Example 191 (Scheme AAAA)—Synthesis of(1S,2S,3S,5R)-3-((4-fluoro-3-methoxy-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (AAAA-6)

Step 1: Synthesis of 2,6-dichloro-5-fluoro-N-(pivaloyloxy)nicotinamide(AAAA-1)

Compound AAAA-1 was prepared in a similar method as step 4 in Scheme FFusing 2,6-dichloro-5-fluoronicotinic acid to give 5.85 g (80% yield) asa white solid. ¹H NMR (400 MHz, CHLOROFORM-d) ä ppm 9.91 (br. s., 1H)8.02 (d, J=5.14 Hz, 1H) 1.37 (s, 9H)

Step 2: Synthesis of6,8-dichloro-5-fluoro-3,4-dihydro-2,7-naphthyridin-1(2H)-one (AAAA-2)

Compound AAAA-2 was prepared from AAAA-1 in a similar method as step 4in Scheme GG using cesium pivalate to give 1.47 g (33% yield) as ayellow solid. LCMS [M+1-2Cl] 167.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm6.13 (br. s., 1H) 3.59 (td, J=6.45, 3.48 Hz, 2H) 3.09 (t, J=6.42 Hz, 2H)

Step 3: Synthesis of8-chloro-5-fluoro-6-methoxy-3,4-dihydro-2,7-naphthyridin-1(2H)-one(AAAA-3)

To a solution of AAAA-2 (200 mg, 0.85 mmol) in 20 mL MeOH was addedsodium methoxide (161 mg, 2.98 mmol, 5.96 mL, 0.5 M), the solution washeated at 60 C for 1 hr. The reaction was concentrated, redissolved inDCM, washed with H₂O twice, DCM was rotavapored, the crude was purifiedby column chromatography with 100% EtOAc to give 100 mg of AAAA-3 (51%yield) as an off white solid. LCMS [M+1] 231.0. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 5.96 (br. s., 1H) 4.09 (s, 3H) 3.52 (td, J=6.39,3.48 Hz, 2H) 3.03 (t, J=6.24 Hz, 2H)

Step 4: Synthesis of tert-butyl8-chloro-5-fluoro-6-methoxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate(AAAA-4)

Compound AAAA-4 was prepared from AAAA-3 in a similar method as step 5in Scheme GG to give 105 mg (76% yield) as a colorless oil. LCMS[M+1-Boc] 217.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.48 (s, 2H) 4.00(s, 3H) 3.63 (t, J=5.93 Hz, 2H) 2.82 (t, J=5.69 Hz, 2H) 1.50 (s, 9H)

Step 5: Synthesis of tert-butyl8-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo [2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-6-methoxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate(AAAA-5)

The mixture of(3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol(SSS-3) (98.0 mg, 0.34 mmol), AAAA-4 (107 mg, 0.339 mmol), cesiumcarbonate (221 mg, 0.677 mmol), tris(dibenzylideneacetone)dipalladium(31.0 mg, 0.0339 mmol) and BINAP (42.2 mg, 0.0677 mmol) in toluene (6.77mL, c=0.05 M) was degassed and purged with N₂ three times. The reactionmixture was heated at 100° C. overnight, LCMS indicated the reactiondidn't complete. Cesium carbonate (221 mg, 0.677 mmol),tris(dibenzylideneacetone)dipalladium (31.0 mg, 0.0339 mmol) and BINAP(42.2 mg, 0.0677 mmol) were added, degassed and continued to heat at100° C. for 2 days. The reaction mixture was cooled to rt, H₂O wasadded, extracted with EtOAc, the crude was concentrated and purified bycolumn chromatography with 85% EtOAc/heptane to give 60 mg (31% yield)yellow oil. LCMS [M+1] 570.1. ¹H NMR (400 MHz, CHLOROFORM-d) ä ppm 8.79(s, 1H) 7.37 (d, J=3.67 Hz, 1H) 6.61 (br. s., 1H) 5.47 (br. s., 1H) 5.35(ddd, J=7.95, 5.26, 2.69 Hz, 1H) 4.98-5.05 (m, 1H) 4.89 (d, J=6.24 Hz,1H) 4.36 (br. s., 2H) 3.99 (s, 3H) 3.56-3.64 (m, 2H) 3.01 (dt, J=14.55,7.27 Hz, 1H) 2.78 (t, J=5.26 Hz, 2H) 2.73 (s, 3H) 2.41-2.52 (m, 1H) 1.60(s, 3H) 1.50 (s, 9H) 1.33 (s, 3H)

Step 6: Synthesis of(1S,2S,3S,5R)-3-((4-fluoro-3-methoxy-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (AAAA-6)

Compound AAAA-6 was prepared from AAAA-5 in a similar method as step 10in Scheme A to give 19.7 mg (33% yield). LCMS [M+1] 430.0. ¹H NMR (400MHz, DMSO-d6) δ ppm 9.68 (br. s., 1H) 9.56 (br. s., 1H) 9.07 (s, 1H)7.99 (br. s., 1H) 7.10 (br. s., 1H) 5.11-5.26 (m, 2H) 4.64 (dd, J=9.05,4.65 Hz, 1H) 4.15 (br. s., 2H) 4.10 (d, J=4.03 Hz, 1H) 3.94 (s, 3H) 3.38(br. s., 2H) 2.91-3.03 (m, 3H) 2.87 (s, 3H) 1.95-2.05 (m, 1H)

Examples 192 & 193 were prepared in a similar fashion to Example 191except that sodium ethoxide in ethanol was used in step 3 of Scheme AAAAfor Example 192 and sodium isopropoxide in isopropanol was used in step3 of Scheme AAAA for Example 193.

Example 192

444.05 [M + 1] (1S,2S,3S,5R)-3-((3-ethoxy-4-fluoro-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR(400 MHz, DMSO-d6) ä ppm 9.50 (br. s., 1 H) 9.40 (br. s., 1 H) 8.99 (br.s., 1 H) 7.93 (br. s., 1 H) 7.04 (br. s., 1 H) 5.19 (q, J = 9.17 Hz, 1H) 5.07-5.13 (m, 1 H) 4.63 (dd, J = 9.05, 4.52 Hz, 1 H) 4.34-4.51 (m, 2H) 4.15 (br. s., 2 H) 4.09 (d, J = 4.16 Hz, 1 H) 3.39 (br. s., 2 H)2.88-3.03 (m, 3 H) 2.83 (s, 3 H) 1.93-2.03 (m, 1 H) 1.33 (t, J = 6.97Hz, 3 H) Example 193

458.00 [M + 1] (1S,2S,3S,5R)-3-((4-fluoro-3-isopropoxy-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d6) ä ppm9.98 (br. s., 1 H) 9.82 (br. s., 1 H) 9.21 (s, 1 H) 8.10 (d, J = 3.67Hz, 1 H) 7.22 (d, J = 3.67 Hz, 1 H) 5.18-5.30 (m, 2 H) 5.10 (d, J = 5.14Hz, 1 H) 4.67 (dd, J = 9.11, 4.46 Hz, 1 H) 4.13 (d, J = 4.52 Hz, 2 H)4.09 (d, J = 4.03 Hz, 1 H) 3.36 (br. s., 2 H) 2.96-3.03 (m, 2 H) 2.94(m, 4 H) 1.96-2.08 (m, 1 H) 1.35 (d, J = 6.1 Hz, 3 H) 1.29 (d, J = 6.1Hz, 3 H)

Scheme BBBB—Synthesis of 2-chloro-6-(difluoromethyl)nicotinic acid(BBBB-4)

Step 1: Synthesis of (E)-4-butoxy-1,1-difluorobut-3-en-2-one (BBBB-1)

Compound BBBB-1 was prepared according to WO20080269059. ¹H NMR (400MHz, CHLOROFORM-d) ä ppm 7.86 (d, J=12.47 Hz, 1H) 5.90 (d, 1H) 5.77 (t,J=56 Hz, 1H) 4.01 (t, J=6.48 Hz, 2H) 1.68-1.80 (m, 2H) 1.41-1.48 (m, 2H)0.97 (t, J=7.40 Hz, 3H)

Step 2: Synthesis of methyl6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (BBBB-2)

Compound BBBB-2 was prepared according to WO20080269059. ¹H NMR (400MHz, DMSO-d6) ä ppm 12.18 (br. s., 1H) 8.20 (d, J=5.87 Hz, 1H) 7.05 (br.s., 1H) 6.86 (t, J=52 Hz, 1H) 3.81 (s, 3H)

Step 3: Synthesis of methyl 2-chloro-6-(difluoromethyl)nicotinate(BBBB-3)

A mixture of BBBB-2 (3340 mg, 16.44 mmol) and phosphors oxychloride (10mL) was heated at 110° C. for 24 hrs, cooled to rt, ice water was added,neutralized by solid KOH. The reaction mixture was extracted with EtOActhree times, the organic layers were combined and concentrated, purifiedby column chromatography with 18% EtOAc/heptane to give 3.27 g (90%yield) of BBBB-3 as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm8.31 (d, J=7.83 Hz, 1H) 7.67 (d, J=7.83 Hz, 1H) 6.61 (t, J=56 Hz, 1H)4.00 (s, 3H); 19F NMR (376 MHz, CHLOROFORM-d) ä ppm −116.82 (s, 1F)

Step 4: Synthesis of 2-chloro-6-(difluoromethyl)nicotinic acid (BBBB-4)

To a solution of BBBB-3 (1160 mg, 5.235 mmol) in 20 mL MeOH was addedsodium hydroxide (1050 mg, 26.2 mmol, 5.23 mL, 5 M), heated at 65° C.for 4 hrs. The reaction mixture was neutralized by 1 N HCl to pH 4, thesolvent was removed, the solid was dried over vacuo and used for nextstep.

Example 194 was made in a similar fashion to Example 191 (Scheme AAAA)except that step 3 is omitted

Example 194

432.05 [M + 1] (1S,2S,3S,5R)-3-((3-(difluoromethyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR(400 MHz, DMSO-d6) ä ppm 10.27 (br. s., 1 H) 10.13 (br. s., 1 H) 9.22(s, 1 H) 8.12 (d, J = 3.67 Hz, 1 H) 7.15-7.28 (m, 2 H) 6.84 (t, J = 56Hz, 1 H) 5.12-5.30 (m, 2 H) 4.69 (dd, J = 8.93, 4.65 Hz, 1 H) 4.08-4.27(m, 3 H) 3.38 (d, J = 9.66 Hz, 2 H) 3.10 (br. s., 2 H) 2.86-3.00 (m, 4H) 1.92-2.10 (m, 1 H)

Examples 195 & 196 were made in a similar fashion to Example 99 inScheme NN using the appropriate NBoc-protected tetrahydroisoquinoline instep 2.

450.2 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6- (difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz,D₂O, HCl salt) δ ppm 8.20 (s, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.12 (s,1H), 7.09 (s, 1H), 6.77 (t, J = 56.0 Hz, 1H), 5.29-5.17 (m, 1H),4.84-4.81 (m, 1H), 4.56 (dd, J = 5.0, 8.8 Hz, 1H), 4.37 (s, 2H), 4.29(d, J = 4.3 Hz, 1H), 3.50 (t, J = 6.3 Hz, 2H), 3.13 (t, J = 6.3 Hz, 2H),3.03 (ddd, J = 7.2, 9.3, 14.9 Hz, 1H), 2.15-2.01 (m, 1H)

468.1 [M + 1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-(difluoromethyl)-5-fluoro-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm9.84 (br s, 2H), 8.76 (br s, 1H), 8.43 (s, 1H), 7.70 (d, J = 1.8 Hz,1H), 7.38-7.02 (m, 2H), 5.07 (q, J = 9.1 Hz, 1H), 4.71-4.56 (m, 1H),4.47 (dd, J = 4.9, 9.4 Hz, 1H), 4.23 (br s, 2H), 3.99 (br d, J = 5.0 Hz,1H), 3.37 (br s, 2H), 3.03-2.95 (m, 2H), 2.93- 2.80 (m, 1H), 1.96-1.81(m, 1H)

Scheme CCCC—Synthesis of tert-butyl8-hydroxy-6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-34)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(CCCC-1)

A solution of NNN-1 (600 mg, 1.29 mmol), 4-bromoisoxazole (286 mg, 1.93mmol), K₂CO₃ (535 mg, 3.87 mmol) and PdCl₂(dppf)-DCM (94 mg, 0.129 mmol)in toluene (2.5 mL) and water (1.5 mL) was stirred under N₂ atmosphereat 75° C. for 16 h. The reaction mixture was then cooled to r.t. Waterwas added and the mixture was extracted with EtOAc (3×5 mL). Thecombined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography with EtOAc/petroleum ether from 15-85% to give acolorless oil CCCC-1 (160 mg, 31%). LCMS [M-tBu+1] 350.9

Step 2—Synthesis of 6-(isoxazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol(CCCC-2)

Compound CCCC-1 (140 mg, 0.344 mmol) was dissolved in DCM (10 mL). Thereaction solution was cooled to 0° C. in an ice bath. BBr₃ (518 mg, 2.07mol) was added. The reaction became from a suspension to a clear yellowsolution. The reaction mixture was stirred at 25° C. for 16 hours. Thereaction was cooled to 0° C. and MeOH (2 mL) was added to the reactiondrop-wise followed by water (20 mL). The reaction solution was washedwith DCM (10 mL×2). The aqueous layer was separated and pH which wasadjusted to pH 9, using NaHCO₃ solid. The final solution of CCCC-2 wasused for the next step directly without further purification (23 mL, aqsoln crude, >99%).

Synthesis of tert-butyl8-hydroxy-6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-34)

MeOH (5 mL) and dioxane (5 mL) were added to the solution of CCCC-2 (23mL aq), then Boc₂O (83 mg, 0.38 mmol) was added to the reactionsolution, the solution was stirred at 25° C. for 16 hours. The pH of thereaction solution was adjusted to pH˜3 by the addition of 1N HCl aq. Thesolution was separated, then aqueous layer was extracted with DCM (10mL). The organic layers were combined and washed with saturated NaCl(20.0 mL). The organic layer was separated, dried and evaporated to givethe crude product, which was purified by flash chromatography, elutedwith petroleum ether/EtOAc from 0-50%, to give the desired product aswhite solid of TP-34 (84 mg, 77% yield over 2 steps). MS [M-Boc+1]217.1; ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 9.32 (s, 1H), 9.02(s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.36 (s, 2H), 3.55 (m, 2H), 2.75(m, 2H), 1.44 (s, 9H)

Example 197 was prepared using the chemistry depicted in Scheme CC andemploying compound TP-34.

448.1 [M + 1] (1S,2S,3S,5R)-3-((6-(isoxazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O) δ ppm 8.98(s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 7.80 (d, J = 3.8 Hz, 1H), 7.15 (s,1H), 7.12-7.07 (m, 2H), 5.35 (q, J = 9.0 Hz, 1H), 4.90-4.86 (m, 1H),4.69-4.65 (m, 1H), 4.39-4.31 (m, 3H), 3.50 (t, J = 6.3 Hz, 2H),3.17-3.01 (m, 3H), 2.89 (s, 3H), 2.28-2.16 (m, 1H)

Scheme DDDD—Synthesis of tert-butyl5-fluoro-8-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-35)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-5-fluoro-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(DDDD-1)

Vial A was charged with t-BuBrettPhos (49 mg, 0.10 mmol), NaOtBu (67.8mg, 0.706 mmol) and ZZZ-10 (220 mg, 0.504 mmol) in dioxane (3 mL). Thevial was degassed with N₂ three times. Then MeOH (81 mg, 2.52 mmol) wasadded to the vial A. Vial B was charged with RockPhosPd3G (85 mg, 0.10mmol) and degassed with N₂ three times followed by addition of dioxane(2 mL) and stirred for 1 min. The precatalyst from vial B wastransferred into vial A and the reaction solution was stirred at 25° C.for 16 hours. EtOAc (10 mL) was added to dilute the solution and washedwith water (5 mL×2). The organic layers were separated, dried andevaporated to give the crude product, which was purified by flashchromatography, eluted with EtOAc/petroleum ether from 0-15% to give thedesired product as colorless oil DDDD-1 (110 mg, 56%). LCMS [M-Boc+1]287.9; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54-7.27 (m, 5H), 6.83 (d, J=7.5Hz, 1H), 5.15 (s, 2H), 4.43-4.26 (m, 2H), 3.82 (s, 3H), 3.53 (t, J=5.8Hz, 2H), 2.71-2.66 (m, 2H), 1.42 (s, 9H)

Step 2—Synthesis of tert-butyl5-fluoro-8-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-35)

Compound DDDD-1 (110 mg, 0.28 mmol) was dissolved in MeOH (3 mL) andEtOAc (1 mL) followed by addition of Pd/C (15 mg, 0.142 mmol). Thesolution was degassed with H₂ four times and stirred at 25° C. for 16hours under an H₂ balloon. The reaction was diluted with DCM (5 mL),filtered, and concentrated to give TP-35 as a white solid (70 mg, 83%).LCMS [M-tBu+1]242.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.58 (s, 1H), 6.46(d, J=7.3 Hz, 1H), 4.28 (s, 2H), 3.74 (s, 3H), 3.55-3.50 (m, 2H), 2.65(m, 2H), 1.43 (s, 9H)

Compound TP-36 was prepared using similar chemistry as Scheme DDDD usingEtOH in Step 1

256 [M − tBu + 1] tert-butyl 6-ethoxy-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.52 (s, 1H), 6.44 (d, J = 7.0 Hz, 1H), 4.28 (s, 2H), 3.99 (q, J = 6.9Hz, 2H), 3.55-3.49 (m, 2H), 2.64 (br t, J = 6.0 Hz, 2H), 1.43 (s, 9H),1.32 (t, J = 6.9 Hz, 3H)

Examples 198 & 199 were prepared using similar chemistry depicted inScheme CC and employing compounds TP-35 & TP-36 respectively.

428.9 [M + 1] (1S,2S,3S,5R)-3-((5-fluoro-6- methoxy-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR(400 MHz, MeOD, HCl salt) δ ppm 9.05 (s, 1H), 8.09 (d, J = 3.7 Hz, 1H),7.25 (d, J = 3.7 Hz, 1H), 6.93- 6.85 (m, 1H), 5.40 (q, J = 9.3 Hz, 1H),4.94-4.90 (m, 1H), 4.81-4.66 (m, 1H), 4.33 (s, 2H), 4.21 (d, J = 5.0 Hz,1H), 3.93 (s, 3H), 3.57-3.47 (m, 2H), 3.14- 3.05 (m, 3H), 3.02 (s, 3H),2.37- 2.24 (m, 1H)

443.1 [M + 1] (1S,2S,3S,5R)-3-((6-ethoxy-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O, HCl salt) δppm 8.82 (s, 1H), 7.84-7.74 (m, 1H), 7.08 (d, J = 3.8 Hz, 1H), 6.70 (d,J = 7.2 Hz, 1H), 5.28 (q, J = 9.1 Hz, 1H), 4.76-4.73 (m, 1H), 4.66-4.58(m, 1H), 4.36-4.20 (m, 3H), 4.18-4.05 (m, 2H), 3.45 (t, J = 6.4 Hz, 2H),3.08- 2.93 (m, 3H), 2.87 (s, 3H), 2.23-2.09 (m, 1H), 1.31 (t, J = 7.0Hz, 3H)

Scheme EEEE—Synthesis of tert-butyl6-(difluoromethoxy)-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-37)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(EEEE-1)

To a solution of ZZZ-10 (500 mg, 1.15 mmol) in dioxane (29 mL) was addedbis(pinacolato)diboron (1.46 g, 5.73 mmol). The solution was degassedwith N₂ for 10 min and cataCXium® A-Pd-G2 (76.6 mg, 0.12 mmol) and KOAc(337 mg, 1.79 mmol) were added to the reaction solution under N₂atmosphere. The reaction was heated at 80° C. for 16 hours. Water (10mL) was added and the reaction was extracted with EtOAc (10 mL×2). Theorganic layers were separated, dried and evaporated to give the crudeproduct, which was purified by flash chromatography, eluted withpetroleum ether/EtOAc 0-20% to give EEEE-1 (78%, 443 mg) as a graysolid. LCMS [M-Boc+1] 384.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.52-7.32(m, 5H), 7.05 (d, J=4.3 Hz, 1H), 5.13 (s, 2H), 4.47 (br s, 2H), 3.57 (brt, J=5.8 Hz, 2H), 2.72-2.66 (m, 2H), 1.43 (s, 9H), 1.30 (s, 12H)

Step 2—Synthesis of tert-butyl8-(benzyloxy)-5-fluoro-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(EEEE-2)

To a solution of EEEE-1 (430 mg, 0.89 mmol) in THF (4 mL) and water (4mL) was added sodium perborate (306 mg, 3.74 mmol) in one portion at RTunder N₂. The reaction solution was stirred at room temperature for 8hours. The mixture was diluted with EtOAc (10 mL) and water (5 mL). Theorganic layer was separated, dried and evaporated to give the crudeproduct, which was purified by flash chromatography, eluted withpetroleum ether/EtOAc 0-20% to give EEEE-2 (150 mg, 45%) as a whitesolid. LCMS [M+Na] 396.

Step 3—Synthesis of tert-butyl8-(benzyloxy)-6-(difluoromethoxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(EEEE-3)

KOH (165 mg, 2.95 mol) was suspended in a mixture of acetonitrile (1 mL)and water (1 mL) and cooled to −20° C. Compound EEEE-2 (110 mg, 0.295mmol) was added portion-wise, followed by diethyl(bromo-difluoromethyl)phosphonate (157 mg, 0.59 mmol) over 15 min. Themixture was warmed to 25° C. for 2 days. Water was added to the reactionsolution and extracted with EtOAc (10 mL×3). The organic layers wereseparated, dried and concentrated to give the crude product, which waspurified by flash chromatography, eluted with petroleum ether/EtOAc0-10%, to give EEEE-3 (100 mg, 80%) as a white solid. LCMS [M-Boc+1]324.

Step 4—Synthesis of tert-butyl6-(difluoromethoxy)-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-37)

To a solution of EEEE-3 (100 mg, 0.23 mmol) in MeOH (5 mL) was addedPd/C (25 mg, 0.024 mmol). The mixture was degassed and purged with H₂three times. The resulting mixture was stirred at r.t. (28° C.) for 16hours. The reaction was diluted with DCM (20 mL) and filtered andconcentrated to give TP-37 as a white solid (75 mg, 95%). LCMS [M-tBu+1]278.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.99 (bs, 1H), 7.31 (t, J=74 Hz,1H), 6.62 (d, J=8 Hz, 1H), 4.33 (s, 2H), 3.55 (t, J=8 Hz, 2H), 2.69 (t,J=8 Hz, 2H), 1.43 (s, 9H)

Example 200 was prepared using similar chemistry depicted in Scheme CCand employing compound TP-37.

465.1 [M + 1] (1S,2S,3S,5R)-3-((6- (difluoromethoxy)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR(400 MHz, D₂O, HCl salt) δ ppm 8.85 (s, 1H), 7.82 (d, J = 3.8 Hz, 1H),7.11 (d, J = 3.8 Hz, 1H), 6.98- 6.58 (m, 2H), 5.32 (q, J = 9.0 Hz, 1H),4.76-4.73 (m, 1H), 4.67-4.62 (m, 1H), 4.35-4.25 (m, 3H), 3.49 (t, J =6.3 Hz, 2H), 3.10-2.96 (m, 3H), 2.90 (s, 3H), 2.24-2.12 (m, 1H)

Scheme FFFF—Synthesis of tert-butyl5-fluoro-8-hydroxy-6-isopropoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-38)

Step 1—Synthesis of tert-butyl8-(benzyloxy)-5-fluoro-6-isopropoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(FFFF-1)

To a solution of EEEE-2 (170 mg, 0.455 mmol) in THF (3 mL) was cooledwith an ice bath and PPh₃ (478 mg, 1.82 mmol) was added under N₂. DIAD(368 mg, 1.82 mmol) was added dropwise and the reaction was stirred at25° C. for 30 min which became a white suspension. Then iPrOH (82.1 mg,1.37 mmol) was added to the reaction solution in one portion and stirredat 15° C. for 16 hours. The mixture was diluted with EtOAc (50 mL) andH₂O (100 mL). The mixture was separated and the aqueous layer wasextracted with EtOAc (50 mL). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by flash chromatography, eluted withpetroleum ether/EtOAc 0-20% to give FFFF-1 (160 mg, 85%) as a colorlessoil. LCMS [M-tBu+1] 270.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.50-7.29 (m,5H), 6.78 (d, J=7.0 Hz, 1H), 5.15 (s, 2H), 4.65-4.53 (m, 1H), 4.38 (brd, J=2.8 Hz, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.74-2.62 (m, 2H), 1.43 (s,9H), 1.23 (d, J=6.0 Hz, 6H)

Step 2—Synthesis of tert-butyl5-fluoro-8-hydroxy-6-isopropoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-38)

To a solution of FFFF-1 (160 mg, 0.385 mmol) in MeOH (5 mL) was addedPd/C (41 mg, 0.039 mmol). The mixture was degassed and purged with H₂three times using a H₂ balloon then stirred at room temperature (28° C.)for 16 hours under a H₂ balloon. The reaction was diluted with DCM (20.0mL) filtered and concentrated to give TP-38 as a yellow solid (118 mg,94%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.50 (br d, J=2.5 Hz, 1H), 6.45(d, J=7.3 Hz, 1H), 4.41 (td, J=6.0, 12.0 Hz, 1H), 4.28 (s, 2H), 3.52 (t,J=5.6 Hz, 2H), 2.64 (br t, J=5.8 Hz, 2H), 1.42 (s, 9H), 1.26 (d, J=6.0Hz, 6H)

Example 201 was prepared using similar chemistry depicted in Scheme CCand employing compound TP-38.

456.9 [M + 1] (1S,2S,3S,5R)-3-((5-fluoro-6- isopropoxy-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol ¹H NMR(400 MHz, D₂O, HCl salt) δ ppm 8.90 (s, 1H), 7.88 (d, J = 3.8 Hz, 1H),7.16 (d, J = 3.8 Hz, 1H), 6.80 (d, J = 6.8 Hz, 1H), 5.37 (q, J = 9.0 Hz,1H), 4.89-4.82 (m, 1H), 4.73-4.63 (m, 2H), 4.35-4.30 (m, 3H), 3.52 (t, J= 6.3 Hz, 2H), 3.14-3.01 (m, 3H), 2.96 (s, 3H), 2.25 (ddd, J = 4.0, 9.4,13.9 Hz, 1H), 1.37-1.30 (m, 6H)

Scheme GGGG—Synthesis of tert-butyl8-cyano-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-39)

Step 1—Synthesis of8-bromo-6-fluoro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (GGGG-2)

To a suspension of GGGG-1 (13.8 g, 43.87 mmol, prepared using referencepatent US2015/64196) in dry THF (400 mL) was added DIPEA (28.3 g, 219mmol) and T3P (50% in EtOAc, 41.9 g, 65.8 mmol) at 0° C. The mixture wasstirred at 0° C. for 10 h then at rt 25° C. for 6 h. The mixture waspoured into water (400 mL) and extracted with EtOAc (400 mL×2). Theextract was washed with brine (300 mL), dried over Na₂SO₄ andconcentrated to give GGGG-2 (9500 mg, 83%) as a light yellow solid. LCMS[M+1] 261.6; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.57 (br s, 1H), 7.44 (dd,J=1.8, 9.5 Hz, 1H), 7.22 (s, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.27 (q, J=5.6Hz, 2H)

Step 2—Synthesis of6-(benzyloxy)-8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(GGGG-3)

To a suspension 60% NaH (6 g, 150 mmol) in dry DMF (140 mL) was added asolution of GGGG-2 (6.5 g, 25 mmol) and BnOH (5.41 g, 50 mmol) in dryDMF (70 mL) at rt 25° C. under N₂, then was stirred at rt 25° C. underN₂ for 16 h. The mixture was poured into ice water (400 mL) in whichsolid was formed. The mixture was filtered. The solid was washed withwater and dried in vacuo to afford GGGG-3 (9500 mg, >99%) as a whitesolid. LCMS [M+1] 347.7; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (br t,J=5.7 Hz, 1H), 7.47 (d, J=6.6 Hz, 2H), 7.42-7.36 (m, 2H), 7.35-7.29 (m,1H), 7.26-7.15 (m, 1H), 6.93 (d, J=1.4 Hz, 1H), 5.19 (s, 2H), 4.12 (t,J=5.5 Hz, 2H), 3.18 (q, J=5.6 Hz, 2H).

Step 3—Synthesis of tert-butyl6-(benzyloxy)-8-bromo-5-oxo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(GGGG-4)

To a solution of GGGG-3 (7.3 g, 21 mmol) in DMF (150 mL) was added Boc₂O(6.86 g, 31.43 mmol), DIPEA (8.13 g, 62.9 mmol) and DMAP (256 mg, 2.1mmol) at rt 25° C. for 2 h. The mixture was poured into water. The solidwas collected by filtration and washed with water. The solid wasdissolved in EtOAc/THF (50 mL/50 mL) and dried over Na₂SO₄ andconcentrated in vacuo to afford crude GGGG-4 (10 g, >99%) as a yellowgum and used directly in the next step without further purification.

Step 4—Synthesis of tert-butyl6-(benzyloxy)-8-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(GGGG-5)

To a solution of GGGG-4 (10 g, 21 mmol) in THF (150 mL) was addedBH₃.Me₂S (8.39 mL, 83.9 mmol) at rt 25° C. The mixture was stirred at60° C. under N₂ for 16 h then stand at rt for 2 days. The reaction wasquenched with MeOH (70 mL) slowly. Then the mixture was refluxed for 16h and concentrated. The crude product was purified by columnchromatography (120 g silica column, EtOAc in petroleum ether from 0% to50%) to afford GGGG-5 (3130 mg, 34%) as a white solid. LCMS [M+23] 456;¹H NMR (400 MHz, CDCl₃) δ ppm 7.52-7.31 (m, 5H), 6.84 (bs, 1H), 6.82(bs, 1H), 5.06 (br s, 2H), 4.64 (br s, 2H), 4.15-4.10 (m, 2H), 3.80 (brs, 2H), 1.29 (br s, 9H)

Step 5—Synthesis of tert-butyl6-(benzyloxy)-8-cyano-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(GGGG-6)

Compound GGGG-5 (680 mg, 1.57 mmol), Zn(CN)₂ (368 mg, 3.13 mmol) andPd(PPh₃)₄(181 mg, 0.157 mmol) in DMF (10 ml) was sparged with N₂ for 10min. The mixture was stirred at 120° C. for 3 h. The mixture was cooled,filtered, and concentrated. The residue was purified by silica gelchromatography eluted with EtOAc in petroleum ether from 0 to 50% toafford GGGG-6 (520 mg, 87%) as a white solid. LCMS [M-Boc+1] 280.9.

Step 6—Synthesis of tert-butyl6-(benzyloxy)-8-carbamoyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(GGGG-7)

To a solution of GGGG-6 (520 mg, 1.37 mmol) and K₂CO₃ (189 mg, 1.37mmol) in DMSO (5 mL) was added 30% H₂O₂(465 mg, 4.1 mmol) at rt 25° C.slowly. Note: gas evolved and exothermic. The mixture was stirred at rt25° C. for 1 h. The mixture was poured into water (10 mL) and filtered.The solid was washed with water. The solid was suspended in MeOH (30 mL)and concentrated in vacuo to afford GGGG-7 (520 mg, 96%) as a whitesolid. LCMS [M+Na]421.

Step 7—Synthesis of tert-butyl8-carbamoyl-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(GGGG-8)

A mixture of GGGG-7 (520 mg, 1.31 mmol) and Pd/C (125 mg) in MeOH/THF(15 mL/15 mL) was degassed with H₂ four times. The mixture was stirredat 25° C. under a H₂ balloon for 16 h. The mixture was filtered andconcentrated in vacuo to afford GGGG-8 (400 mg, 99%) as a white solid.¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 9.85 (br s, 1H), 7.80 (br s,1H), 7.22 (br s, 1H), 7.11-6.97 (m, 1H), 6.92 (br s, 1H), 4.57 (br s,2H), 4.20-4.03 (m, 2H), 3.68 (br s, 2H), 1.42-1.13 (m, 9H)

Step 8—Synthesis of tert-butyl8-cyano-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-39)

To a suspension of GGGG-8 (100 mg, 0.324 mol) and pyridine (128 mg, 1.62mol) in anhydrous DCM (2 mL) was added Tf₂O (275 mg, 0.973 mol) at 0° C.and stirred for 0.5 h. The reaction mixture was warmed to 25° C. andstirred for 16 h. The mixture was concentrated in vacuo to dryness. Theresidue was dissolved in MeOH (3 mL), followed by K₂CO₃ (300 mg). Themixture was stirred at rt 25° C. for 16 h. The reaction was filtered andpurified by prep-TLC (petroleum ether/EtOAc 1:1) to afford TP-39 (55 mg,58%) as a white solid. LCMS [M-Boc+1]190.8; ¹H NMR (400 MHz, DMSO-d₆,rotamers) δ ppm 10.47 (br s, 1H), 6.83 (br s, 2H), 4.70-4.51 (m, 2H),4.22-4.18 (m, 2H), 3.69 (br s, 2H), 1.46-1.21 (m, 9H)

Scheme HHHH—Synthesis of tert-butyl8-fluoro-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-40)

To a solution of HHHH-1 (prepared using similar method as steps 1-4 inScheme GGGG using 2-(2-aminoethoxy)-4,6-difluorobenzoic acid, 1980 mg,5.302 mmol) in MeOH (74 mL) was added 10% wet Pd/C (590 mg) at 25° C.The mixture was stirred at 25° C. under a H₂ balloon for 1.2 hours. Thereaction was filtered and concentrated to yield TP-40 (1420 mg, 95%) asa white solid. LCMS [M-Boc+1] 184.8 ¹H NMR (400 MHz, DMSO-d₆, rotamers)δ ppm 10.60-9.69 (bs, 1H), 6.34-6.30 (m, 1H), 6.26-6.12 (m, 1H),4.63-4.39 (m, 2H), 4.23-4.01 (m, 2H), 3.75-3.58 (m, 2H), 1.46-1.20 (m,9H); ¹H NMR (400 MHz, DMSO-d₆, Variable temp 80° C.) δ ppm 6.33 (br d,J=10.3 Hz, 1H), 6.19 (dd, J=2.3, 10.3 Hz, 1H), 4.53 (s, 2H), 4.19-4.06(m, 2H), 3.69 (br t, J=4.4 Hz, 2H), 1.36 (s, 9H)

Scheme IIII—Synthesis of tert-butyl8-chloro-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-41)

Step 1—Synthesis of8-chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-ol (IIII-2)

To a solution of IIII-1 (prepared using similar method as steps 1-3 inScheme GGGG using 2-(2-aminoethoxy)-4-chloro-6-fluorobenzoic acid, 1000mg, 3.292 mmol) in dry THF (11 mL) was added BH₃.Me₂S (2.63 mL, 26.3mmol) at rt 25° C. under N₂. After addition, the mixture was heated at70° C. for 16 hours. The mixture was cooled to rt (25° C.) and quenchedwith MeOH (3 mL). The mixture was concentrated as a white solid. Thecrude product was dissolved in conc HCl (13.7 mL) and heated at 110° C.for 16 hours. The mixture was concentrated to obtain IIII-2 (860mg, >99%) as a light yellow solid which was used in next step directly.LCMS [M+1] 199.7

Step 2—Synthesis of tert-butyl8-chloro-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-41)

To a solution of IIII-2 (1171 mg, 3.3 mmol) in MeOH (21 mL) was addedTEA (3.58 mL, 25.6 mmol) and Boc₂O (1.32 g, 6.02 mmol) then stirred atr.t. for 2 hours. The mixture was concentrated in vacuum to get crudeproduct (1032 mg) as white solid. The crude product purified bycombi-flash (EtOAc/Petroleum ether=0-50%) to afford TP-41 (520 mg, 30%)as a white solid. LCMS [M-tBu+1] 243.6; ¹H NMR (400 MHz, DMSO-d₆,rotamers) δ ppm 10.13 (s, 1H), 6.61-6.57 (m, 1H), 6.45 (bs, 1H),4.61-4.46 (m, 2H), 4.25-4.05 (m, 2H), 3.66 (br s, 2H), 1.42-1.27 (m, 9H)

Examples 202-204 were prepared using similar chemistry depicted inScheme CC and employing compounds TP-39, TP-40 & TP-41 respectively

422.2 [M + 1] 6-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentyl)oxy)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- carbonitrile ¹H NMR (400 MHz, D₂O,HCl salt) δ ppm 8.86 (s, 1H), 7.85 (d, J = 3.8 Hz, 1H), 7.25 (d, J = 1.0Hz, 1H), 7.20 (d, J = 1.3 Hz, 1H), 7.11 (d, J = 3.8 Hz, 1H), 5.35 (q, J= 9.2 Hz, 1H), 4.86-4.80 (m, 2H), 4.60 (q, J = 14.8 Hz, 2H), 4.43- 4.26(m, 3H), 3.66 (t, J = 4.9 Hz, 2H), 3.15-3.04 (m, 1H), 2.91 (s, 3H),2.28- 2.18 (m, 1H)

414.9 [M + 1] (1S,2S,3S,5R)-3-((8-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD, HCl salt)δ ppm = 9.07 (s, 1H), 8.12 (d, J = 4.0 Hz, 1H), 7.25 (d, J = 3.8 Hz,1H), 6.86 (dd, J = 2.5, 10.8 Hz, 1H), 6.59 (dd, J = 2.4, 9.4 Hz, 1H),5.40 (q, J = 9.3 Hz, 1H), 4.77 (dd, J = 5.0, 9.3 Hz, 2H), 4.62- 4.50 (m,2H), 4.34 (tdt, J = 4.5, 9.3, 13.6 Hz, 2H), 4.25 (d, J = 5.0 Hz, 1H),3.65 (t, J = 4.6 Hz, 2H), 3.13-3.04 (m, 1H), 3.02 (s, 3H), 2.36 (ddd, J= 4.4, 9.7, 14.3 Hz, 1H)

431.1 [M + 1] (1S,2S,3S,5R)-3-((8-chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD) δ ppm 8.65(s, 1H), 7.59 (d, J = 3.7 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.78 (d, J= 3.6 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 5.24 (q, J = 9.0 Hz, 1H),4.73-4.66 (m, 2H), 4.21 (d, J = 5.1 Hz, 1H), 4.16-4.04 (m, 4H),3.22-3.17 (m, 2H), 3.00 (ddd, J = 7.5, 9.2, 14.4 Hz, 1H), 2.74 (s, 3H),2.29-2.15 (m, 1H)

Scheme JJJJ—Synthesis of tert-butyl8-(difluoromethyl)-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-42)

Step 1—Synthesis of tert-butyl6-(benzyloxy)-8-formyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(JJJJ-1)

Ref. Manabe, K. et al. Org. Lett., 2013, 5370-5373. A reaction vial wasadded a solution of GGGG-5 (1.64 g, 3.62 mmol) in anhydrous DMF (18 mL)and N-formylsaccharin (1200 mg, 5.66 mmol), G3 Xantphos (107 mg, 0.113mmol) and DIPEA (634 mg, 4.91 mmol). The mixture was sparged with N₂ for4 min. To the above solution was added Et₃SiH (571 mg, 4.91 mmol) at 0°C. After the addition, the resulting mixture was sparged with N₂ for 5min and then heated at 75° C. for 16 hours. The reaction mixture waspartitioned between EtOAc and water. The organic layer was separated andthe aqueous layer was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to afford the crude product which was purified via flashcolumn (20 g, gel, EtOAc:petroleum ether 1%-14%) to afford JJJJ-1 (730mg, 53%) as a white solid. ¹H NMR (400 MHz, CDCl₃, rotamers) δ ppm 9.87(br s, 1H), 7.59-7.30 (m, 5H), 7.21 (bs, 1H), 7.14 (bs, 1H), 5.16 (br s,2H), 4.75 (br s, 2H), 4.24-4.17, (m, 2H), 3.85 (br s, 2H), 1.54-1.13 (m,9H)

Step 2—Synthesis of tert-butyl6-(benzyloxy)-8-(difluoromethyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(JJJJ-2)

To a solution of JJJJ-1 (930 mg, 2.43 mmol) in anhydrous DCM (49 mL) wasadded DAST (3.91 g, 24.3 mmol) at 0° C. under N₂. After the addition,the reaction mixture was warmed to room temperature (32° C.) and stirredat this temperature for 16 hours. The reaction solution was diluted inDCM (50 mL) and sat. aq NaHCO₃ and stirred until CO₂ evolution ceased.The reaction mixture was partitioned between DCM and H₂O. The organiclayer was separated, washed with brine, dried over Na₂SO₄ andconcentrated to afford the crude product which was purified via flashcolumn (EtOAc:petroleum ether 1%-15%) to afford JJJJ-2 (530 mg, 54%) asa white solid. ¹H NMR (400 MHz, CDCl₃, rotamers) δ ppm 7.58-7.29 (m,5H), 6.82 (bs, 1H), 6.79 (bs, 1H), 6.54 (t, J=54 Hz, 1H), 5.12 (br s,2H), 4.72 (br s, 2H), 4.21-4.07 (m, 2H), 3.83 (br s, 2H), 1.54-1.13 (m,9H)

Step 3—Synthesis of tert-butyl8-(difluoromethyl)-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-42)

To a solution of JJJJ-2 (530 mg, 1.31 mmol) in MeOH (13 mL) was addedPd/C (139 mg, 0.0163 mmol). The mixture was degassed and purged with H₂three times, then stirred at rt (35° C.) for 16 hours. The reaction wasfiltered through celite and concentrated. The residue was lyophilized toremove the residual solvent to give TP-42 (360 mg, 87%) as a whitesolid. LCMS [M-tBu+1] 259.7; ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm10.21-9.89 (m, 1H), 7.02-6.47 (m, 3H), 4.65-4.49 (m, 2H), 4.22-4.04 (m,2H), 3.74-3.62 (m, 2H), 1.46-1.11 (m, 9H)

Example 205 was prepared using similar chemistry depicted in Scheme CCand employing compound TP-42.

447.1 [M + 1] (1S,2S,3S,5R)-3-((8-(difluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O, HCl salt) δppm 8.90 (s, 1H), 7.89 (d, J = 3.9 Hz, 1H), 7.15 (d, J = 3.7 Hz, 1H),7.08 (s, 1H), 7.02 (s, 1H), 6.77 (t, J = 55.8 Hz, 1H), 5.37 (q, J = 9.0Hz, 1H), 4.91- 4.84 (m, 1H), 4.73-4.68 (m, 1H), 4.60 (dd, J = 13.4, 30.7Hz, 2H), 4.45-4.24 (m, 3H), 3.67 (t, J = 4.8 Hz, 2H), 3.15- 3.04 (m,1H), 2.90 (s, 3H), 2.33-2.20 (m, 1H)

Scheme KKKK—Synthesis of tert-butyl6-hydroxy-8-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-43)

Step 1—Synthesis of tert-butyl6-(benzyloxy)-8-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(KKKK-1)

A solution of GGGG-5 (200 mg, 0.46 mmol) in dioxane (9.21 mL) wasdegassed with N₂ for 5 min. Then bis(tri-tert-butylphosphine)Pd(0) (23.5mg, 0.05 mmol) and (Me)₂Zn (0.921 mL, 0.92 mmol) was then added to thereaction solution and heated at 90° C. for 16 hours. The reactionsolution was poured into EtOAc and 1N HCl (20 mL:20 mL). The mixture wasseparated and the water layer was washed with EtOAc (20 mL×2). Theorganic layers were separated, dried and evaporated to give the crudeproduct, which was purified by flash chromatography, eluted withpetroleum ether/EtOAc from 0-25%, to afford KKKK-1 (160 mg, 94%) as ayellow solid.

LCMS [M+Na] 392.1; ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 7.57-7.30(m, 5H), 6.62 (bs, 1H), 6.39 (s, 1H), 5.09 (bs, 2H), 4.65-4.60 (m, 2H),4.17-4.04 (m, 2H), 3.68 (br s, 2H), 2.22 (s, 3H), 1.42-1.15 (m, 9H)

Step 2—Synthesis of tert-butyl6-hydroxy-8-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-43)

Compound KKKK-1 (160 mg, 0.433 mmol) was dissolved in MeOH (8.00 mL).Then Pd/C was added to the reaction solution, then was degassed with H₂four times and stirred at 30° C. under H₂ (balloon) for 16 hours. DCM(20 mL) was added to dilute the reaction solution, then filtered andconcentrated to give the crude product, which was purified by flashchromatography, eluted with petroleum ether/EtOAc from 0-25%, to giveTP-43 (100 mg, 83%) as a white solid. LCMS [M-Boc+1] 179.9; ¹H NMR (400MHz, DMSO-d₆, rotamers) δ ppm 9.41 (s, 1H), 6.37-6.35 (m, 1H), 6.22-6.20(m, 1H), 4.58-4.42 (m, 2H), 4.13-3.95 (m, 2H), 3.70-3.59 (m, 2H), 2.13(s, 3H), 1.41-1.27 (m, 9H)

Example 206 was prepared using similar chemistry depicted in Scheme CCand employing compound TP-43

411.1 [M + 1] (1S,2S,3S,5R)-3-((8-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O, HCl salt) δppm 8.89 (s, 1H), 7.87 (d, J = 3.8 Hz, 1H), 7.14 (d, J = 3.8 Hz, 1H),6.78 (s, 1H), 6.71 (s, 1H), 5.38 (q, J = 9.0 Hz, 1H), 4.77-4.70 (m, 2H),4.62-4.47 (m, 2H), 4.40-4.22 (m, 3H), 3.63 (t, J = 4.8 Hz, 2H), 3.09(ddd, J = 7.3, 9.3, 14.7 Hz, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.28-2.16(m, 1H)

Scheme LLLL—Synthesis of tert-butyl(S)-6-hydroxy-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-44)

Step 1—Synthesis of methyl(S)-2-(benzyloxy)-6-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate(LLLL-1)

To a solution of methyl 2-(benzyloxy)-6-hydroxybenzoate (2.80 mg, 10.8mmol) in THF (40.0 mL) were added PPh₃ (7.11 g, 27.1 mmol) in an icebath under N₂. DIAD (5.48 g, 27.1 mmol) was added to the above mixturedrop-wise then stirred at 25° C. for 40 min. Then tert-butyl(S)-(1-hydroxypropan-2-yl)carbamate (5.70 g, 32.5 mmol) in dry THF (20.0mL) was added and the reaction stirred at 28° C. for 16 hours. Themixture was diluted with EtOAc (50 mL) and H₂O (100 mL). The mixture wasseparated and the aqueous layer was extracted with EtOAc (50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to yield crude product which waspurified by ISCO (120 g silica gel, petroleum ether:EtOAc=4:1) to yieldLLLL-1 (3.50 g, 78%) as a colorless gum. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.42-7.35 (m, 4H), 7.34-7.29 (m, 2H), 6.83-6.75 (m, 2H), 6.71 (d, J=8.5Hz, 1H), 5.16 (s, 2H), 3.95-3.92 (m, 1H), 3.80-3.70 (m, 5H), 1.43-1.34(m, 9H), 1.08 (d, J=6.5 Hz, 3H)

Step 2—Synthesis of methyl (S)-2-(2-aminopropoxy)-6-(benzyloxy)benzoate(LLLL-2)

To a solution of LLLL-1 (4.30 g, 10.3 mmol) in DCM (10 mL) was addedHCl(g)/dioxane (˜4N, 20 mL) at 0° C. The mixture was stirred 25° C. for2 hours. The mixture was concentrated to yield LLLL-2 as the HCl salt(4.00 g, >99%) as a yellow solid, which was used in next step directly.

Step 3—Synthesis of (S)-2-(2-aminopropoxy)-6-(benzyloxy)benzoic acid(LLLL-3)

To a suspension of LLLL-2 (4.0 g, 3.17 mmol) in MeOH (60 mL) and water(12 mL) was added LiOH.H₂O (3.46 g, 82.4 mmol) at 25° C. The mixture wasstirred 75° C. for 15 hours. The pH of the solution was adjusted to pH-3with 1N. The solution was evaporated to give the crude product LLLL-3(3.10 g, >99%) as a white solid which was used for the next stepdirectly without further purification.

Step 4—Synthesis of(S)-6-(benzyloxy)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(LLLL-4)

To a suspension of LLLL-3 (4.00 g, 5.77 mmol) in dry THF (60 mL) wasadded DIPEA (3.73 g, 28.9 mmol) and T3P (50% in EtOAc, 7.35 g, 11.5mmol) at 0° C. The mixture was stirred 25° C. for 15 hours. The reactionwas not complete and DIPEA (3.73 g, 28.9 mmol) and T3P (50% in EtOAc,7.35 g, 11.5 mmol) was and stirred for another 16 hours. EtOAc (40.0 mL)was added to dilute the solution. The solution was washed with 1N HCl(30 mL), saturated aq NaHCO₃ (30 mL) and brine (30 mL). The organiclayers were separated, dried and evaporated to give the crude productwhich was purified by flash chromatography, eluted with petroleumether/EtOAc from 0-50% to give the desired product LLLL-4 (900 mg, 55%)as a white solid. LCMS [M+1]283.9; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.09(d, J=6.3 Hz, 1H), 7.51-7.44 (m, 2H), 7.41-7.25 (m, 4H), 6.99-6.91 (m,1H), 6.68 (dd, J=0.9, 8.2 Hz, 1H), 5.15 (s, 2H), 3.97 (dd, J=4.3, 10.3Hz, 1H), 3.86-3.77 (m, 1H), 3.46-3.44 (m, 1H), 1.05 (d, J=6.5 Hz, 3H)

Step 5—Synthesis of tert-butyl(S)-6-(benzyloxy)-3-methyl-5-oxo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(LLLL-5)

To a solution of LLLL-4 (900 mg, 3.18 mmol) in DMF (20.0 mL) were addedDIPEA (1.23 g, 9.53 mmol) and DMAP (38.8 mg, 0.318 mmol) at 25° C. Boc₂O(1.04 mg, 4.76 mmol) and the reaction mixture was stirred at 25° C. for16 hours. The mixture was diluted with ice-water (20 mL) and extractedwith EtOAc (20 mL×2). The combined organic layers were washed with brine(30 mL×5), dried over Na₂SO₄ and filtered, concentrated in vacuo toafford crude which was purified by ISCO (4 g silica gel, EtOAc:petroleumether=18%-20%) to yield LLLL-5 (720 mg, 59%) as a white solid and useddirectly in the next step. LCMS [M-Boc+1] 238.9

Step 6—Synthesis of tert-butyl(S)-6-(benzyloxy)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(LLLL-6)

To a solution of LLLL-5 (720 mg, 1.88 mmol) in THF (20 mL) was addedBH₃.Me₂S (10 M, 0.751 mL, 7.51 mmol) at 0° C. The mixture was stirred at74° C. under N₂ for 2 hours. The reaction was quenched with MeOH (5 mL)slowly and heated at reflux for 16 hours. The mixture was concentratedto give the crude product which was purified by combi flash (40 g silicacolumn, EtOAc in petroleum ether from 9-10% to afford LLLL-6 (530 mg,76.4%) as a colorless gum. LCMS [M-Boc+1] 270.0; ¹H NMR (400 MHz,DMSO-d₆, rotamers) δ ppm 7.54-7.32 (m, 5H), 7.06 (t, J=8.2 Hz, 1H), 6.70(d, J=8.3 Hz, 1H), 6.46 (dd, J=0.8, 8.3 Hz, 1H), 5.35-4.97 (m, 3H),4.54-4.30 (m, 1H), 4.24-4.02 (m, 3H), 1.39-1.22 (m, 9H), 1.06 (m, 3H)

Step 7—Synthesis of tert-butyl(S)-6-hydroxy-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-44)

To a solution of LLLL-6 (530 mg, 1.43 mmol) in MeOH (10.0 mL) was addedwet 10% Pd/C (100 mg). The reaction solution was stirred at 30° C. undera H₂ balloon for 16 h. Then the mixture was filtered through celite,washed with MeOH, and concentrated to give TP-44 (360 mg, 90%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 9.61-9.49 (m,1H), 6.87 (t, J=8.2 Hz, 1H), 6.44 (d, J=7.8 Hz, 1H), 6.26 (dd, J=1.0,8.0 Hz, 1H), 5.23-4.94 (m, 1H), 4.54-4.28 (m, 1H), 4.15-4.00 (m, 3H),1.39-1.25 (m, 9H), 1.06 (d, J=6.8 Hz, 3H)

Compound TP-45 was prepared using similar conditions as Scheme LLLLusing tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate in step 1

179.9 [M − Boc + 1] tert-butyl (R)-6-hydroxy-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate ¹H NMR (400 MHz, CDCl₃,rotamers) δ ppm 8.15- 7.57 (m, 1H), 6.81 (br t, J = 7.9 Hz, 1H), 6.43(br d, J = 8.0 Hz, 1H), 6.39- 6.20 (m, 1H), 4.96 (d, J = 16.1 Hz, 1H),4.71-4.31 (m, 1H), 4.17-4.03 (m, 2H), 3.87 (br dd, J = 3.8, 12.5 Hz,1H), 1.53-1.35 (m, 9H), 1.32 (br d, J = 6.8 Hz, 3H)

Examples 207 & 208 were prepared using similar chemistry depicted inScheme CC and employing compounds TP-44 & TP-45, respectively

410.9 [M + 1] (1S,2S,3S,5R)-3-(((S)-3-methyl- 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) δ ppm8.65 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H),6.83-6.69 (m, 2H), 6.59 (d, J = 8.0 Hz, 1H), 5.32 (d, J = 4.0 Hz, 1H),5.19-5.07 (m, 2H), 4.59-4.50 (m, 2H), 4.35 (d, J = 14.9 Hz, 1H), 4.19(dd, J = 2.4, 11.8 Hz, 1H), 4.01 (br s, 1H), 3.59 (br d, J = 14.7 Hz,1H), 3.39 (br s, 1H), 3.15 (br d, J = 6.5 Hz, 1H), 2.89-2.77 (m, 1H),2.65 (s, 3H), 2.45-2.50 (m, 1H), 2.03- 1.91 (m, 1H), 0.97 (d, J = 6.5Hz, 3H)

411.2 [M + 1] (1S,2S,3S,5R)-3-(((R)-3-methyl- 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O, HCl salt) δppm 8.81 (s, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.32 (t, J = 8.3 Hz, 1H),7.07 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 7.8 Hz,1H), 5.31 (q, J = 8.9 Hz, 1H), 4.84-4.73 (m, 3H), 4.42 (dd, J = 2.5,13.3 Hz, 1H), 4.34 (dd, J = 1.4, 4.9 Hz, 1H), 4.21 (d, J = 14.6 Hz, 1H),3.93-3.72 (m, 2H), 3.11-2.94 (m, 1H), 2.88 (s, 3H), 2.24-2.11 (m, 1H),1.28 (d, J = 6.5 Hz, 3H)

Scheme MMMM—Synthesis of tert-butyl(R)-6-hydroxy-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-46)

Step 1—Synthesis of tert-butyl(R)-6-(benzyloxy)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(MMMM-1)

To a compound MMMM-1 (prepared in a similar method as steps 1-5 inScheme LLLL using tert-butyl (R)-(2-hydroxypropyl)carbamate), 500 mg,(1.5 mmol) in dry THF (10.0 mL) was added LAH (233 mg, 6.14 mmol) at 25°C. The mixture was stirred at 75° C. for 2 h. The reaction was cooled tor.t., in which water (2.0 mL) was added to the reaction followed byBoc₂O (670 mg, 3.07 mmol). The mixture was stirred for 2.5 h at r.t.,then water was added and the reaction extracted with EtOAc (10 mL×3),dried with Na₂SO₄, concentrated to give the crude product which waspurified by ISCO (20 g, silica gel, EtOAc/petroleum ether=15%) to yieldMMMM-2 (520 mg, 92%) as a colorless gum. LCMS [M-Boc+1] 269.9

Step 2—Synthesis of tert-butyl(R)-6-hydroxy-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate(TP-46)

Compound MMMM-2 (520 mg, 1.3 mmol) dissolved in MeOH (10 mL) was addedPd/C (100 mg, 0.940 mmol). The reaction solution was stirred at 25° C.under H₂ for 2 h. Then the mixture was filtered through celite, washedwith MeOH, and concentrated. The residue was purified by ISCO (20 g,silica gel, EtOAc/petroleum ether=25%) to afford TP-46 (234 mg, 67%) asa white solid. LCMS [M-Boc+1] 179.7; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.55(s, 1H), 7.06 (t, J=8.1 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.67-6.55 (m,1H), 4.64 (d, J=14.7 Hz, 1H), 4.15-4.07 (m, 1H), 3.90 (br d, J=14.4 Hz,1H), 3.84-3.76 (m, 1H), 3.29 (dd, J=8.9, 14.5 Hz, 1H), 1.41 (s, 9H),1.29 (d, J=6.5 Hz, 3H)

Compound TP-47 was prepared in a similar method as Scheme MMMM usingtert-butyl (S)-(2-hydroxypropyl)carbamate

179.8 [M − Boc + 1] tert-butyl (S)-6-hydroxy-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate ¹H NMR (400 MHz, CDCl₃)δ ppm 7.56 (s, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H),6.66-6.59 (m, 1H), 4.63 (d, J = 14.3 Hz, 1H), 4.14-4.07 (m, 1H), 3.89(br d, J = 14.6 Hz, 1H), 3.85-3.76 (m, 1H), 3.29 (dd, J = 8.8, 14.3 Hz,1H), 1.40 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H)

Examples 209 & 210 were prepared using similar chemistry depicted inScheme CC and employing compounds TP-46 & TP-47, respectively.

411.2 [M + 1] (1S,2S,3S,5R)-3-(((R)-2-methyl- 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, D₂O, HCl salt) δppm 8.80 (s, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H),7.06 (d, J = 3.8 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.0 Hz,1H), 5.28 (q, J = 9.0 Hz, 1H), 4.84-4.75 (m, 3H), 4.32 (dd, J = 1.6, 4.9Hz, 1H), 4.26-4.13 (m, 2H), 3.56 (br d, J = 12.5 Hz, 1H), 3.34 (dd, J =10.5, 13.8 Hz, 1H), 3.06-2.94 (m, 1H), 2.87 (s, 3H), 2.23-2.09 (m, 1H),1.38 (d, J = 6.5 Hz, 3H)

410.9 [M + 1] (1S,2S,3S,5R)-3-(((S)-2-methyl- 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD, HCl salt)δ ppm 9.04 (s, 1H), 8.09 (d, J = 3.8 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H),7.22 (d, J = 3.8 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz,1H), 5.42 (q, J = 9.2 Hz, 1H), 4.81-4.72 (m, 3H), 4.33 (d, J = 16 Hz,1H), 4.29-4.22 (m, 2H), 3.63-3.60 (m, 1H), 3.42-3.39 (m, 1H), 3.14-3.05(m, 1H), 3.01 (s, 3H), 2.33 (ddd, J = 4.4, 9.8, 14.2 Hz, 1H), 1.48 (d, J= 6.5 Hz, 3H)

Scheme NNNN—Synthesis oftert-butyl-6-(difluoromethyl)-5-fluoro-8-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-48)

Step 1: Synthesis of 2-(benzyloxy)-4-bromo-5-fluorobenzoic acid (ZZZ-6)

To a round bottom flask, equipped with a magnetic stirbar, was addedlithium tert-butoxide (3.81 g, 47.6 mmol) and DMSO (119 mL, 0.2M). Theflask was fitted with a fendenser and benzyl alcohol (4.95 mL, 47.6mmol) was added. The flask was placed in a heating mantle and heated to80° C. for 5 minutes. The flask was removed and ZZZ-1 (5.64 g, 23.8mmol) was added. The flask was returned to the heating mantle adn heatedat 80° C. for 17 hours. The reaction was removed from the heating mantleand allowed to cool to rt. The solution was poured into 1.2 L of waterand acidified with 48 mL of 1M HCl aq. resulting in a tan precipitate.The solids were filtered and washed with water. The solids werecollected and dried in a vacuum oven for 3.5 hours at 80° C. to affordthe title compound ZZZ-6 (7.21 g, 93%) as a light tan solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 13.10 (br. s., 1H), 7.61 (d, J=8.8 Hz, 1H), 7.57 (d,J=5.6 Hz, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.44-7.36 (m, 2H), 7.35-7.28 (m,1H), 5.22 (s, 2H).

Step 2: Synthesis of2-(benzyloxy)-4-bromo-5-fluoro-N-(pivaloyloxy)benzamide (ZZZ-7)

To a round bottom flask, equipped with a magnetic stirbar, was addedZZZ-6 (5.73 g, 17.6 mmol) and THF (176 mL, 0.1M). The solution wascooled to 0° C. and T3P (24.7 g, 38.8 mmol) was added as a 50% wt.solution in EtOAc. After the addition, the reaction mixture was stirredfor 30 min at 25° C. To the above solution was added DIPEA (18.4 mL, 106mmol) followed by FF-3 (5.18 g, 19.4 mmol). After the addition, thereaction mixture was stirred at 25° C. for 1 hour. The reaction wasquenched with water, diluted with EtOAc, and transferred to a separatoryfunnel. The phases were separated and the organic phase was washed with1 portion 10% citric acid, 1 portion sat. NaHCO₃, and 1 portion brine.The organic extract was then dried (MgSO₄), filtered, and concentratedunder vacuum. The crude residue was purified via flash columnchromatography (12g SiO₂, Isco, 100% Hept. to 100% EtOAc, 9 mLfractions) to afford the title compound ZZZ-7 (6.24 g, 83%) as a whitesolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.79 (s, 1H), 7.94 (d,J=8.9 Hz, 1H), 7.52-7.35 (m, 5H), 7.27-7.23 (m, 1H), 5.26 (s, 2H), 1.34(s, 9H).

Step 3: Synthesis of8-(benzyloxy)-6-bromo-5-fluoro-4-methyl-3,4-dihydroisoquinolin-1(2H)-one(NNNN-1)

To a 80 mL steel reactor was added ZZZ-7 (4.00 g, 9.43 mmol), Cesiumpivalate (4.41 g, 18.9 mmol), [Cp^(t)RhCl₂]₂(166 mg, 0.236 mmol) andtrifluoroethanol (47 mL, 0.2M). The reactor was purged with nitrogen 3times followed by 3 cycles of purging with propylene gas. The reactionwas heated to 40° C. under 4 bar of propylene gas for 3 days. Thesolution was quenched with NaHCO₃ aq. and transferred to a separatoryfunnel with DCM. The phases were separated and the aqueous phase wasextracted with 2 portions DCM. The combined organic extracts were dried(MgSO₄), filtered, and concentrated under vacuum. The crude residue waspurified via flash column chromatography (40g SiO₂, Isco, 100% Hept. to10% MeOH/EtOAc, 25 mL fractions) to afford the title compound NNNN-1(2.27 g, 66%, 9:1 r.r.) as a brown solid. LCMS [M+H]=364 observed. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (d, J=7.5 Hz, 2H), 7.47-7.36 (m,2H), 7.35-7.28 (m, 1H), 7.13 (d, J=5.5 Hz, 1H), 5.92 (d, J=3.8 Hz, 1H),5.27-5.19 (m, 1H), 5.16-5.10 (m, 1H), 3.69 (dd, J=4.0, 12.7 Hz, 1H),3.40-3.30 (m, 1H), 3.23 (ddd, J=1.3, 6.0, 12.6 Hz, 1H), 1.36 (d, J=7.1Hz, 3H).

Step 4: Synthesis oftert-butyl-8-(benzyloxy)-6-bromo-5-fluoro-4-methyl-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate(NNNN-2)

To a round bottom flask, equipped with a magnetic stirbar and containingNNNN-1 (1.20 g, 3.29 mmol) was added DCM (11.0 mL, 0.3M), DIPEA (0.86mL, 4.94 mmol), (Boc)₂O (1.08 g, 4.94 mmol), and DMAP (60.4 mg, 0.494mmol). The flask was fitted with a findenser and placed in a heatingblock. The reaction was heated at 40° C. for 16 hours. The flask wasremoved from the heating block and allowed to cool to rt. The reactionwas quenched with water and transferred to a separatory funnel with DCM.The phases were separated and the aqueous phase was extracted with 2portions DCM. The combined organic extracts were dried (MgSO₄),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (40g SiO₂, Isco, 100% Hept to 100%EtOAc, 9 mL fractions) to afford the title compound NNNN-2 (1.41 g, 92%)as a white foam. LCMS [M+H-Boc]=364 observed. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.55 (d, J=7.5 Hz, 2H), 7.44-7.35 (m, 2H), 7.32 (d,J=7.3 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 5.28-5.20 (m, 1H), 5.18-5.09 (m,1H), 4.21 (dd, J=2.2, 13.2 Hz, 1H), 3.61 (dd, J=3.2, 13.1 Hz, 1H),3.39-3.27 (m, 1H), 1.59 (s, 9H), 1.33 (d, J=7.1 Hz, 3H).

Step 5: Synthesis oftert-butyl-8-(benzyloxy)-6-bromo-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(NNNN-3)

To a round bottom flask, equipped with a magnetic stirbar and containingNNNN-2 (1.41 g, 3.04 mmol), was added THF (15 mL, 0.2M) and boranedimethylsulfide complex (1.44 mL, 15.2 mmol). The flask was fitted witha findenser and transferred to a heating block. The reaction was heatedat 70° C. for 30 minutes. The flask was removed from the heating blockand allowed to cool gradually to rt. The reaction was quenched bydropwise addition of methanol until the evolution of gas was complete,followed by dilution with heptane. The solution was concentrated undervacuum. The crude residue was purified via flash column chromatography(40g SiO₂, Isco, 100% Hept to 10% EtOAc/Hept. to 100% EtOAc, 9 mLfractions) to afford the title compound NNNN-3 (1.13 g, 82%) as a whitefoam. LCMS [M+H-Boc]=350 observed. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm7.47-7.30 (m, 5H), 6.93 (d, J=5.5 Hz, 1H), 5.18-4.79 (m, 3H), 4.26-3.96(m, 2H), 3.28-2.95 (m, 2H), 1.51 (s, 9H), 1.25 (d, J=6.8 Hz, 3H).

Step 6: Synthesis oftert-butyl-8-(benzyloxy)-5-fluoro-6-formyl-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(NNNN-4)

Note: nBuLi was titrated, THF was dried over activated 4 A molecularsieves, and syringe needles were oven dried @ 85 C under vacuum prior touse.

A round bottom flask containing NNNN-3 (1.00 g, 2.22 mmol) was driedunder high vacuum overnight, equipped with a magnetic stirbar, andpurged with argon under dynamic vacuum. To the flask was added THF (11.0mL, 0.2M) and the solution was cooled to −78° C. with a AcMe/dry icebath. To the cooled solution was added n-butyl lithium (1.7 mL, 2.30mmol) dropwise to induce metal-halogen exchange. The reaction wasstirred at −78° C. under argon for 30 minutes.

Note: The reaction turns bright orange upon dropwise addition of nBuLi.

To the solution was added DMF (0.26 mL, 3.4 mmol) dropwise at −78° C. Atthis stage, the ice bath was removed and the reaction was allowed towarm gradually to room temperature.

Note: The reaction turns pale yellow upon warming to room temperature.

The reaction was reverse quenched by addition of the reaction solutionto sat. NH₄Cl aq. (10 mL). The aqueous phase was extracted with 4portions DCM. The combined organic extracts were dried (MgSO₄),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (24 g SiO₂, Isco, 100% Hept. to 100%EtOAc, 20 mL fractions) to afford the title compound NNNN-4 (885mg, >95%) as a white waxy solid. LCMS [M+H-Boc]=300 observed. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.48-7.31 (m, 5H), 7.21 (d,J=5.3 Hz, 1H), 5.29-4.87 (m, 3H), 4.32-4.03 (m, 2H), 3.35-3.18 (m, 1H),3.17-3.00 (m, 1H), 1.52 (s, 9H), 1.29 (d, J=6.8 Hz, 3H).

Step 7: Synthesis oftert-butyl-8-(benzyloxy)-6-(difluoromethyl)-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(NNNN-5)

A scintillation vial, equipped with a magnetic stirbar and containingNNNN-4 (1.77 g, 4.43 mmol), was purged with argon under dynamic vacuum.The vial was charged with DCM (44 mL, 0.1M) and the solution was cooledto 0° C. followed by the dropwise addition of DAST (1.46 mL, 11.1 mmol).The ice bath was removed and the solution was allowed to gradually warmto rt. The reaction was stirred under argon for 24 hours. During thecourse of the reaction, 2 additional aliquots of DAST (1.46 mL, 11.1mmol) were added at 12 and 17 hours respectively to drive conversion(7.5 equivalents of DAST total). The reaction was quenched via thedropwise addition of sat. NaHCO₃ aq. CAUTION: Rapid evolution of CO₂ gasoccurs during quench. The contents of the vial were transferred to aseparatory funnel with DCM and diluted with water. The phases wereseparated and the aqueous phase was extracted with 3 portions DCM. Thecombined organic extracts were dried (MgSO₄), filtered, and concentratedunder vacuum. The crude residue was purified via flash columnchromatography (40g SiO₂, Isco, 100% Hept. to 100% EtOAc, 20 mLfractions) to afford the title compound NNNN-5 (1.59 g, 85%) as a paleyellow gum. LCMS [M+H-Boc]=322 observed. ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.49-7.29 (m, 5H), 6.95 (d, J=5.3 Hz, 1H), 6.89 (t, J=55.1 Hz,1H), 5.22-4.90 (m, 3H), 4.27-4.02 (m, 2H), 3.28-2.96 (m, 2H), 1.51 (s,9H), 1.26 (d, J=7.0 Hz, 3H).

Step 8: Synthesis oftert-butyl-6-(difluoromethyl)-5-fluoro-8-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-48)

To a 500 mL round bottom flask, equipped with a magnetic stirbar andcontaining NNNN-5 (1.65 g, 3.91 mmol), was added methanol (78 mL,0.05M). To the solution was added Pd/C 10 wt % (417 mg, 0.391 mmol) andthe solution was purged with hydrogen gas under dynamic vacuum. Thereaction was stirred vigorously under 1 atm of hydrogen for 1.5 hours.The reaction was filtered over celite, the solids washed with DCM, andthe filtrate concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (24g SiO₂, Isco, 100% Hept. to 100%EtOAc, 20 mL fractions) to afford the title compound TP-48 (1.15 g, 88%)as a white foam. LCMS [M+H-Boc]=232 observed. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.00-6.65 (m, 2H), 5.22-4.79 (m, 1H), 4.29-3.94 (m,2H), 3.28-2.95 (m, 2H), 1.58-1.51 (m, 9H), 1.23 (d, J=7.0 Hz, 3H).

Scheme OOOO—Synthesis oftert-butyl-5-fluoro-8-hydroxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-49)

Step 1: Synthesis of7-(benzyloxy)-10-fluoro-1,4a,5,10b-tetrahydro-1,4-methanophenanthridin-6(4H)-one(OOOO-1)

To a round bottom flask, equipped with a magnetic stirbar, was addedVVV-4 (2.29 g, 6.63 mmol), cesium pivalate (3.10 g, 13.3 mmol),[Cp*RhCl₂]₂(20.5 mg, 0.0332 mmol), and trifluoroethanol (33 mL, 0.2M).The flask was capped with a rubber septum and norbornadiene (0.74 mL,7.29 mmol) was added. The flask was placed in a heating mantle and thereaction was heated to 45° C. for 40 minutes. The flask was removed fromthe heating block and allowed to cool to rt. The solution was dilutedwith water followed by DCM and the phases were separated. The organicphase was washed with 1 portion water, dried (MgSO₄), filtered, andconcentrated under vacuum. The crude residue was further dried underhigh vacuum to afford the title compound OOOO-1 as an orange solid whichwas used in the next step without further purification. LCMS [M+H]=336observed.

Step 2: Synthesis of 8-(benzyloxy)-5-fluoroisoquinolin-1(2H)-one(OOOO-2)

To a microwave vial, equipped with a magnetic stirbar, was added OOOO-1(˜6.63 mmol) as a solution in toluene (15 mL, 0.44M). The vial wassealed with a teflon cap and placed in the microwave reactor. Thereaction was heated to 130° C. for 1 hour. The solution was transferredto a round bottom flask with DCM and concentrated under vacuum. Thecrude residue was further dried under high vacuum to afford the titlecompound OOOO-2 (1.79 g, >95%) as a brown solid which was used in thenext step without further purification. LCMS [M+H]=270 observed. ¹H NMR(400 MHz, DMSO-d6) δ ppm 11.07 (br. s., 1H), 7.62 (d, J=7.2 Hz, 2H),7.46 (t, J=9.3 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.33-7.27 (m, 1H),7.24-7.19 (m, 1H), 7.00 (dd, J=4.2, 9.0 Hz, 1H), 6.45 (d, J=7.1 Hz, 1H),5.20 (s, 2H).

Step 3: Synthesis of 8-(benzyloxy)-1-chloro-5-fluoroisoquinoline(OOOO-3)

To a reaction vial, equipped with a magnetic stirbar, was addedbenzyltriethylammonium chloride (846 mg, 3.71 mmol) and OOOO-2 (500 mg,1.86 mmol) as a solution in acetonitrile (19 mL, 0.1M). The vial wassealed with a teflon cap and dimethylaniline (0.35 mL, 2.79 mmol) wasadded followed by the dropwise addition of phosphorous oxychloride (1.04mL, 11.1 mmol). The vial was placed in a heating block and heated at 80°C. for 10 minutes. The solution was concentrated and the crude residuewas transferred to a separatory funnel with DCM and diluted with water.The phases were separated and the aqueous phase was extracted with 2portions DCM. The combined organic extracts were dried (MgSO₄),filtered, and concentrated under vacuum. The crude residue was purifiedvia flash column chromatography (24g SiO₂, Isco, 100% Hept. to 100%EtOAc, 9 mL fractions) to afford the title compound OOOO-3 (465 mg, 87%)as a light orange solid. LCMS [M+H]=288 observed. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.32 (d, J=5.6 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.56(d, J=7.2 Hz, 2H), 7.48-7.28 (m, 4H), 6.97 (dd, J=4.3, 8.7 Hz, 1H), 5.27(s, 2H).

Step 4: Synthesis of 8-(benzyloxy)-5-fluoro-1-methylisoquinoline(OOOO-4)

To an oven dried reaction vial, equipped with a magnetic stirbar andcooled under a stream of argon, was added OOOO-3 (422 mg, 1.47 mmol) andPd(PPh₃)₄(84.7 mg, 0.0733 mmol). The vial was capped with a rubberseptum and purged with argon under dynamic vacuum. To the vial was addedTHF (7.33 mL, 0.2M) followed by the dropwise addition of dimethyl zinc(2.20 mL, 4.40 mmol). The vial was sealed with a teflon cap and placedin a heating block. The reaction was refluxed at 75° C. for 1 hour. Thevial was removed from the heating block and allowed to cool to rt. Thereaction was carefully quenched by the dropwise addition of sat. NH₄Claq. The solution was transferred to a separatory funnel with DCM. Thephases were separated and the aqueous phase was extracted with 3portions DCM. The combined organic extracts were washed with 1 portionbrine, dried (MgSO₄), filtered, and concentrated under vacuum. The cruderesidue was purified via flash column chromatography (12g SiO₂, Isco,100% Hept. to 100% EtOAc, 9 mL fractions) to afford (356 mg) of a lightorange solid. The isolated material was re-subjected to flash columnchromatography (12g SiO₂, Isco, 100% Hept. to 10% MeOH/EtOAc, 9 mLfractions) to afford the title compound OOOO-4 (310 mg, 79%) as a whitesolid. The isolated solid was used in the next step with ˜80% puritybased on ¹H NMR analysis. LCMS [M+H]=268 observed. ¹H NMR (400 MHz,CHLOROFORM-d) d=8.43 (d, J=5.7 Hz, 1H), 7.68 (d, J=5.9 Hz, 1H), 7.50 (d,J=7.1 Hz, 2H), 7.47-7.39 (m, 3H), 7.22 (t, J=8.9 Hz, 1H), 6.86 (dd,J=4.3, 8.6 Hz, 1H), 5.22 (s, 2H), 3.10 (s, 3H).

Step 5: Synthesis of5-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (OOOO-5)

To a steel reactor was added OOOO-4 (250 mg, 0.935 mmol), PtO₂ (42.5 mg,0.187 mmol), ethanol (15 mL) and acetic acid (0.5 mL). The solution washydrogenated under 45 psi of hydrogen gas at rt for 20 hours. Thesolution was filtered through celite and the solids washed with ethanol.The filtrate was concentrated under vacuum to give the title compoundOOOO-5 (178 mg, >95%) as slight yellow solid which was used in the nextstep without further purification. ¹H NMR (400 MHz, METHANOL-d4) δ ppm6.92-6.85 (m, 1H), 6.71-6.65 (m, 1H), 4.69 (q, J=6.7 Hz, 1H), 3.51-3.37(m, 2H), 3.06-2.84 (m, 2H), 1.62 (d, J=6.8 Hz, 3H)

Step 6: Synthesis of tert-butyl5-fluoro-8-hydroxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(TP-49)

To a round bottom flask, equipped with a magnetic stirbar and containingOOOO-5 (130 mg, 0.717 mmol), was added methanol (10 mL, 0.07M), (Boc)₂O(157 mg, 0.717 mmol), and trimethylamine (145 mg, 1.43 mmol). Thereaction was stirred at 25° C. for 2.5 hours. The solution wasconcentrated under vacuum. The crude residue was purified via flashcolumn chromatography (20g SiO₂, Isco, 25% EtOAc/pet ether) to affordthe title compound TP-49 (158 mg, 78%) as a white solid. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 6.81-6.69 (m, 1H), 6.55 (dd, J=4.4, 8.7 Hz,1H), 5.54-5.20 (m, 1H), 4.32-4.03 (m, 1H), 3.36-3.07 (m, 1H), 2.86-2.66(m, 2H), 1.51 (s, 9H), 1.43 (d, J=6.6 Hz, 3H).

Examples 211-214 were made in a similar fashion as Examples 182 & 183(Scheme YYY) starting with the appropriate racemictetrahydroisoquinoline in step 1 and separating the diastereomers priorto the final deprotection.

463 observed [M + H] (1S,2S,3S,5R)-3-((6- (difluoromethyl)-5-fluoro-4-methyl-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin- 7-yl)cyclopentane-1,2-diol Example 211 (Isomer 1)-¹H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 8.83(s, 1H), 7.80 (br s, 1H), 7.14-6.80 (m, 3H), 5.32 (q, J = 9.0 Hz, 1H),4.78 (br s, 2H), 4.48-4.37 (m, 1H), 4.32-4.18 (m, 2H), 3.50-3.32 (m,3H), 3.10-2.98 (m, 1H), 2.89 (s, 3H), 2.24- 2.13 (m, 1H), 1.33 (d, J =6.8 Hz, 3H). Example 212 (Isomer 2)-¹H NMR (400 MHz, DEUTERIUM OXIDE) δppm 8.83 (s, 1H), 7.80 (d, J = 3.7 Hz, 1H), 7.14- 6.77 (m, 3H), 5.32 (q,J = 9.1 Hz, 1H), 4.80- 4.78 (m, 1H), 4.64 (br dd, J = 5.0, 8.9 Hz, 1H),4.47-4.35 (m, 1H), 4.30-4.20 (m, 2H), 3.51-3.30 (m, 3H), 3.09-2.95 (m,1H), 2.88 (s, 3H), 2.26- 2.10 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H).

413 observed [M + H] (1S,2S,3S,5R)-3-((5- fluoro-1-methyl-1,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)cyclopentane-1,2- diol Example 213 (Isomer1)-¹H NMR (400 MHz, METHANOL-d4) δ ppm 9.04 (s, 1H), 8.03 (d, J = 3.3Hz, 1H), 7.23 (d, J = 3.4 Hz, 1H), 7.14- 6.96 (m, 2H), 5.39 (q, J = 9.1Hz, 1H), 4.79 (br dd, J = 4.9, 9.3 Hz, 3H), 4.27 (br d, J = 4.2 Hz, 1H),3.67-3.48 (m, 2H), 3.19-2.95 (m, 6H), 2.29 (br t, J = 10.1 Hz, 1H), 1.75(d, J = 6.5 Hz, 3H). Example 214 (Isomer 2)-¹H NMR (400 MHz,METHANOL-d4) ? = 9.03 (s, 1H), 8.08 (d, J = 3.4 Hz, 1H), 7.25 (d, J =3.4 Hz, 1H), 7.14- 7.01 (m, 2H), 5.37 (q, J = 9.2 Hz, 1H), 4.82- 4.73(m, 3H), 4.22 (br d, J = 4.5 Hz, 1H), 3.63- 3.54 (m, 2H), 3.20- 2.99 (m,6H), 2.38 (ddd, J = 3.9, 9.7, 13.8 Hz, 1H), 1.75 (d, J = 6.6 Hz, 3H)

Examples 215 & 216 were made in a similar fashion as Examples 182 & 183(Scheme YYY) starting with the appropriate racemictetrahydroisoquinoline in step 1, performing aminolysis in a similarfashion to step 4 (Scheme NN), and separating the diastereomers prior tothe final deprotection.

482 observed [M + H] (1S,2S,3R,5S)-3-(4- amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((6- (difluoromethyl)-5-fluoro-4-methyl-1,2,3,4- tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-diol Example 215 (Isomer 1)-¹H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm8.24 (s, 1H), 7.30 (s, 1H), 7.21-6.88 (m, 2H), 5.36-5.21 (m, 1H), 4.87(br d, J = 1.8 Hz, 1H), 4.57 (br dd, J = 5.1, 8.7 Hz, 1H), 4.51-4.42 (m,1H), 4.36-4.23 (m, 2H), 3.58-3.43 (m, 3H), 3.14-2.99 (m, 1H), 2.17-2.06(m, 1H), 1.41 (d, J = 6.5 Hz, 3H). Example 216 (Isomer 2)-¹H NMR (400MHz, DEUTERIUM OXIDE) δ ppm 8.22 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H),7.21- 6.85 (m, 2H), 5.30- 5.16 (m, 1H), 4.86 (br d, J = 1.5 Hz, 1H),4.56 (dd, J = 5.0, 9.0 Hz, 1H), 4.46 (br d, J = 16.8 Hz, 1H), 4.37-4.20(m, 2H), 3.61-3.41 (m, 3H), 3.02 (ddd, J = 7.5, 9.2, 14.9 Hz, 1H), 2.18-2.02 (m, 1H), 1.53- 1.34 (m, 3H).

BIOLOGICAL EXAMPLES

Biochemical Assay Methods

Compounds were solubilized in DMSO and serially diluted, using 3-folddilutions, into 100% DMSO at a concentration 50-fold greater than thedesired assay concentration. Following dilution, 1 ul was added to anempty 96-well microtiter plate. PRMT5/MEP50 protein complex was combinedwith H4(1-21) peptide (SGRGKGGKGLGKGGAKRHRKV) in PRMT5 assay buffer (50mM Tris pH 8.5, 50 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, 1 mM TCEP) and 44 ulwas added to the microtiter plate containing compound.S-Adenosyl-L-methionine (SAM) was prepared by combining ³H labelled SAMwith unlabelled SAM in PRMT5 assay buffer such that the final SAMconcentration was 10 uM and the specific activity was 0.2 uCi/ul. Thereaction was initiated by adding 5 ul of SAM stock to the microtiterplate. The final reaction conditions were 10 nM PRMT5/MEP50 complex, 200nM peptide and 1 uM SAM. Following a 25 minute incubation at roomtemperature, the reaction was stopped with the addition of 100 uL of 20%TCA. The 3H-peptide product was captured using a 96-well filter plate(MSIPN4B, Millipore) and washed 5 times with PBS buffer. Scintillationfluid (100 ul) was added to the dried filter plate and counted in aliquid scintillation counter. IC₅₀ values were determined by fitting thedata to the standard 4-parameter dose response equation using Pfizerproprietary software.

Results for the biochemical assay of examples are summarized in Table 1,shown as IC₅₀ values in μM.

TABLE 1 PRMT5 Enzyme Inhibition Example PRMT5 IC50 (uM) 1 0.510 2 8.3823 0.032 4 0.681 5 0.025 6 0.423 7 0.120 8 3.389 9 0.060 10 0.941 110.020 12 0.478 13 0.016 14 0.719 15 >200 16 >200 17 2.767 18 3.701 190.064 20 17.09 21 0.217 22 0.003 23 0.572 24 0.071 25 0.056 26 0.704 270.449 28 5.769 29 >200 30 >200 31 0.466 32 15.69 33 3.580 34 59.47 350.150 36 2.697 37 0.266 38 15.71 39 0.114 40 2.045 41 0.046 42 1.387 430.879 44 16.97 45 46 0.297 47 29.47 48 0.005 49 0.105 50 18.89 51 0.67652 0.906 53 0.006 54 0.126 55 0.002 56 0.002 57 0.048 58 0.289 59 5.74360 >200 61 2.124 62 0.025 63 1.057 64 >200 65 >200 66 0.004 67 >20068 >200 69 >200 70 13.56 71 0.069 72 0.022 73 6.885 74 63.29 75 37.85 76143.59 77 0.065 78 0.001 79 0.083 80 0.130 81 1.666 82 0.991 83 0.020 840.002 85 0.002 86 0.004 87 0.002 88 0.001 89 0.001 90 0.002 91 0.001 920.001 93 0.001 94 0.001 95 0.006 96 0.019 97 0.065 98 0.011 99 0.002 1000.001 101 0.001 102 0.001 103 0.001 104 0.001 105 0.001 106 0.002 1070.001 108 0.001 109 0.001 110 0.008 111 0.028 112 0.004 113 0.001 1140.004 115 0.147 116 0.257 117 0.005 118 0.002 119 0.001 120 0.001 1210.001 122 0.003 123 0.002 124 0.002 125 0.001 126 0.001 127 0.009 1280.001 129 0.001 130 0.001 131 0.001 132 0.002 133 0.001 134 0.001 13510.22 136 11.11 137 0.123 138 0.002 139 0.001 140 0.017 141 3.931 1420.011 143 0.006 144 0.077 145 0.011 146 0.027 147 0.024 148 0.002 1490.069 150 0.071 151 0.078 152 0.008 153 0.005 154 0.001 155 0.002 1560.107 157 0.004 158 >200 159 0.005 160 0.009 161 0.201 162 0.042163 >200 164 0.004 165 0.002 166 0.003 167 168 169 0.037 170 0.001 1710.014 172 1.285 173 0.003 174 175 0.005 176 0.002 177 0.004 178 0.002179 0.001 180 0.003 181 0.001 182 0.002 183 0.001 184 0.001 185 0.006186 0.012 187 0.971 188 0.004 189 0.604 190 0.001 191 0.001 192 0.055193 0.180 194 0.001 195 0.001 196 0.001 197 0.001 198 0.001 199 0.091200 0.001 201 0.310 202 0.001 203 0.001 204 0.002 205 0.001 206 0.002207 0.024 208 0.008 209 0.005 210 0.001 211 0.001 212 0.001 213 0.001214 0.008 215 0.001 216 0.001

A549 Proliferation Assay

A549 lung adenocarcinoma cells (American Type Culture Collection) weremaintained in DMEM growth media (Life Technologies) supplemented with10% v/v heat inactivated fetal bovine serum (Sigma) and cultured at 37°C., 5% CO₂. Exponentially growing A549 cells were plated in 96-wellblack tissue culture treated plates (Corning) at a density of 2500cells/ml in a volume of 100 μl culture media and allowed to adhereovernight at 37° C., 5% CO₂. The following day, compound plates wereprepared by making nine-point 3.3-fold dilutions in DMSO with a topconcentration of 10 mM. Compounds were further diluted in culture mediaand 11 μl was added to the cells (final top assay concentration was 10μM and DMSO was 0.2%). Cells were incubated with compound at 37° C., 5%CO₂ for 7 days with media and compound replacement on day 4. Cellviability was assayed on Day 7 by adding 100 μl Cell Titer Glo (Promega)reagent to the plate to measure the amount of ATP present in the cells.Luminescence was read using the Envision 2104 Multilabel Reader (PerkinElmer). The 50% inhibitory concentration (IC₅₀) was determined using a4-parameter fit model normalized to the DMSO control in dose response.

Results for the A549 proliferation assay of examples are summarized inTable 2, shown as IC50 values in μM.

TABLE 2 A549 Cell Proliferation IC50 Example A549 Cell IC50 (uM) 3 1.0985 0.932 11 1.394 13 0.971 19 1.072 22 0.135 25 1.673 48 0.192 53 0.22755 3.168 56 0.378 66 6.813 77 1.123 78 1.615 84 0.500 85 0.920 86 1.84087 0.296 88 0.545 89 0.195 90 0.948 91 0.119 92 0.312 93 0.140 94 0.11595 8.130 98 1.494 99 0.728 100 0.185 101 0.112 102 0.192 103 0.201 1040.460 105 0.383 106 3.847 107 0.991 108 0.163 109 0.067 114 3.940 1177.141 118 4.840 119 0.556 120 0.442 121 0.938 122 4.478 123 0.452 1243.828 125 0.637 126 0.498 128 0.597 129 1.045 130 0.983 131 0.482 1322.751 133 0.443 134 0.640 138 1.477 139 0.637 140 2.380 143 1.402 1467.069 148 4.883 154 0.002 159 5.199 160 0.405 164 3.859 165 0.766 1660.039 169 0.743 173 3.572 175 3.229 176 1.563 177 2.374 178 4.057 1800.159 181 1.140 182 2.180 183 0.136 184 1.398 186 9.533 188 6.473 1900.007 191 7.017 194 0.111 195 0.022 196 0.003 197 3.461 198 3.822 2000.140 202 1.765 203 0.677 204 0.720 205 0.248 206 6.548 207 1.479 2101.546 211 0.014 212 0.002 213 1.198 214 1.081 215 0.001 216 0.006

Molecular Biology

Gene encoding full length PRMT5 open reading frame (ORF) was fuseddirectly at Ala2 to MDYKDDDDKGRAT sequence encoding Flag tag (SEQ ID: 1)and full length untagged MEP50 (SEQ ID: 2) were codon optimized formammalian expression and synthetized by GenScript, Piscataway, N.J.Synthetized genes were cloned into insect cell expression vectorpFASTBac Dual (Life Technologies) using standard restriction enzymebased cloning procedures. In the final construct PRMT5 ORF was undercontrol of polyhedrin promoter (polH) while MEP50 ORF was under controlof p10 promoter. Additionally, MEP50 (SEQ ID: 2) was subcloned intopFASTBac1 vector using standard restriction enzyme based cloningprocedures.

Protein Expression

Viruses were generated using standard Bac-to-Bac viral generationprotocols (Life Technologies) and amplified to high-titer passage two(P2) stocks. Protein over expression was conducted in exponentiallygrowing Sf21 cells infected at 2×106 with P2 viral stock at MOI=1 ofPRMT5-Mep50 dual construct virus and Mep50 construct virus at 1:1 ratio.The co-expression protocol was used to supplement additional Mep50 forFlagPRMT5-Mep50 heterodimer formation. Cells were harvested at 72 h postinfection by centrifugation and frozen pellet was stored at −80° C.

Protein Purification

FlagPRMT5-Mep50 complex was purified from cell lysate using Flagaffinity chromatrography. Cell were lyzed in 50 mM Tris 7.5, 200 mMNaCl, 10% glycerol, 0.25 mM TCEP supplemented with EDTA-free proteaseinhibitor cocktail (Roche). 1.5 ml of lysis buffer was added per 1 g offrozen pellet. The clarified lysate was obtained by centrifugation ofcell lysate at 10,000 g for 1 h at 4 C. 5 ml of Anti-FLAG M2 Agarose(Sigma) for 3 h to isolate was added to the clarified lysate to isolateFlagPRMT5-Mep50. Following batch binding for 3 h at 4 C, Flag resinbound to FlagPRMT5-Mep50 washed with 20 column volumes (CV) of 50 mMTris 7.5, 200 mM NaCl, 10% glycerol, 0.25 mM TCEP followed by elution ofFlagPRMT5-Mep50 complex using 3 CV of 50 mM Tris 7.5, 200 mM NaCl, 10%glycerol, 0.25 mM TCEP supplemented with 200 ug/ml of FLAG Peptide(DYKDDDDK). FlagPRMT5-Mep50 was further purified using S300 26/600column (GE Healthcare) pre-equilibrated with 2 CV of 25 mM Tris pH7.5,150 mM NaCl, 5% glycerol, 0.5 mM TCEP buffer. Peak fractions containingFlagPRMT5-Mep50 complex were concentrated to 1.6 mg/ml, flash frozen insmall aliquots using liquid nitrogen and stored at −80° C.

Sequences

SEQ ID: 1 MDYKDDDDKGRATAAMAVGGAGGSRVSSGRDLNCVPEIADTLGAVAKQGFDFLCMPVFHPRFKREFIQEPAKNRPGPQTRSDLLLSGRDWNTLIVGKLSPWIRPDSKVEKIRRNSEAAMLQELNFGAYLGLPAFLLPLNQEDNTNLARVLTNHIHTGHHSSMFWMRVPLVAPEDLRDDIIENAPTTHTEEYSGEEKTWMWWHNFRTLCDYSKRIAVALEIGADLPSNHVIDRWLGEPIKAAILPTSIFLTNKKGFPVLSKMHQRLIFRLLKLEVQFIITGTNHHSEKEFCSYLQYLEYLSQNRPPPNAYELFAKGYEDYLQSPLQPLMDNLESQTYEVFEKDPIKYSQYQQAIYKCLLDRVPEEEKDTNVQVLMVLGAGRGPLVNASLRAAKQADRRIKLYAVEKNPNAVVTLENWQFEEWGSQVIVVSSDMREWVAPEKADIIVSELLGSFADNELSPECLDGAQHFLKDDGVSIPGEYTSFLAPISSSKLYNEVRACREKDRDPEAQFEMPYVVRLHNFHQLSAPQPCFTFSHPNRDPMIDNNRYCTLEFPVEVNTVLHGFAGYFETVLYQDITLSIRPETHSPGMFSWFPILFPIKQPITVREGQTICVRFWRCSNSKKVWYEWAVTAPVCSAIHNPTGRSYTIGL* SEQ ID: 2MRKETPPPLVPPAAREWNLPPNAPACMERQLEAARYRSDGALLLGASSLSGRCWAGSLWLFKDPCAAPNEGFCSAGVQTEAGVADLTWVGERGILVASDSGAVELWELDENETLIVSKFCKYEHDDIVSTVSVLSSGTQAVSGSKDICIKVWDLAQQVVLSSYRAHAAQVTCVAASPHKDSVFLSCSEDNRILLWDTRCPKPASQIGCSAPGYLPTSLAWHPQQSEVFVFGDENGTVSLVDTKSTSCVLSSAVHSQCVTGLVFSPHSVPFLASLSEDCSLAVLDSSLSELFRSQAHRDFVRDATWSPLNHSLLTTVGWDHQVVHHVVPTEPLPAPGPASVTE*

1-25. (canceled)
 26. A method of treating abnormal cell growth in amammal, the method comprising administering to the mammal atherapeutically effective amount of the compound(1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol,having the structure:

or a pharmaceutically acceptable salt thereof.
 27. A method of treatingcancer in a mammal, the method comprising administering to the mammal atherapeutically effective amount of the compound(1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol,having the structure:

or a pharmaceutically acceptable salt thereof.
 28. The method of claim27, wherein the cancer is lung cancer, bone cancer, pancreatic cancer,skin cancer, cancer of the head or neck, cutaneous or intraocularmelanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of theanal region, stomach cancer, colon cancer, breast cancer, uterinecancer, carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, prostatecancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of thebladder, cancer of the kidney or ureter, renal cell carcinoma, carcinomaof the renal pelvis, neoplasms of the central nervous system (CNS),primary CNS lymphoma, spinal axis tumors, brain stem glioma, orpituitary adenoma.
 29. The method of claim 27, wherein the cancer islymphoma.
 30. The method of claim 27, wherein the cancer is coloncancer.
 31. The method of claim 27, wherein the cancer is esophagealcancer.
 32. The method of claim 27, wherein the cancer is stomachcancer.
 33. The method of claim 27, wherein the cancer is lung cancer.34. The method of claim 27, wherein the cancer is breast cancer.
 35. Themethod of claim 27, wherein the cancer is ovarian cancer.
 36. The methodof claim 27, wherein the cancer is bladder cancer.
 37. The method ofclaim 27, wherein the cancer is cervical cancer or uterine cancer. 38.The method of claim 27, wherein the cancer is pancreatic cancer.
 39. Themethod of claim 27, wherein the cancer is leukemia.